Metabolic inflexibility, defined as the inability to respond or adapt to metabolic demand, is now recognised as a driving factor behind many pathologies associated with obesity and the metabolic syndrome. Adipose tissue plays a pivotal role in the ability of an organism to sense, adapt to and counteract environmental changes. It provides a buffer in times of nutrient excess, a fuel reserve during starvation and the ability to resist cold-stress through non-shivering thermogenesis. Recent advances in single-cell RNA sequencing combined with lineage tracing, transcriptomic and proteomic analyses have identified novel adipocyte progenitors that give rise to specialised adipocytes with diverse functions, some of which have the potential to be exploited therapeutically. This review will highlight the common and distinct functions of well-known adipocyte populations with respect to their lineage and plasticity, as well as introducing the most recent members of the adipocyte family and their roles in whole organism energy homeostasis. Finally, this article will outline some of the more preliminary findings from large data sets generated by single-cell transcriptomics of mouse and human adipose tissue and their implications for the field, both for discovery and for therapy.

Introduction

The dramatic rise in the incidence of metabolic disease has promoted a major increase in adipose tissue research over the last decade. The loss of metabolic flexibility in lipid-storing tissues is a driving force behind complications in obesity, type II diabetes and cardiovascular disease that together contribute to the metabolic syndrome, one of the leading causes of death worldwide [1–3]. Whilst dietary intervention and promotion of an active lifestyle remain arguably the most effective preventative measures to combat these diseases, access to high-calorie, nutrient-poor foods and an increasingly sedentary societal infrastructure are increasing the demand for alternative therapeutic approaches. Previous efforts aimed at developing drugs to treat aspects of the metabolic syndrome focused on reducing caloric intake, both through appetite suppression and restricting absorption of lipids and carbohydrates in the gut. More recent efforts have begun to approach the problem from the other side of the energy-balance scale, through increasing metabolic rate.

At the forefront of this research is the promotion of adipose tissue-mediated thermogenesis, both in classical brown adipose tissue (BAT) and through the formation of brown-like adipocytes in white adipose tissue (WAT) depots. Whilst the ability to induce brown adipose characteristics in white adipocytes is now widely accepted, little is understood about the origin of these cells, and even less so the importance of their origin to their function. Advances in RNA sequencing technology has provided evidence for the existence of multiple adipocyte subtypes, defined not merely by morphology, but by their cellular origin and ability to adapt to metabolic stress. Lineage tracing has allowed us to begin to dissect the heterogeneity of adipose depots, with some proving to be far more complex than previously anticipated. Combining these powerful techniques, together with complimentary -omics, substrate labelling and advanced imaging strategies, has brought adipocyte biology to the forefront of metabolic research.

These exciting findings, though in their infancy, raise an important question deserving of investigation; does lineage contribute to the function and plasticity of an adipocyte? This article will discuss the structural and functional characteristics of both classical and novel adipocyte subtypes, their developmental origin and how these may come together to regulate whole organism energy homeostasis. The therapeutic potential of these different cell types is yet to be determined, but with an increasing interest in the adipocyte field from both basic and translational perspectives, the next decade of adipocyte research is well placed to deliver exciting new findings.

Adipocytes: masters of energy homeostasis

Until recently, white adipocytes were thought of as metabolically inert lipid storage cells, and were often referred to simply as fat cells. Now it is recognised that adipocytes encompass a highly heterogeneous, plastic and metabolically active diverse array of cell types. Adipocytes are found both in discrete depots and interspersed in other organs. Different types of adipocytes can be distinguished according to their appearance (colour) together with their gross cellular characteristics (e.g. number of mitochondria, size and number of lipid droplets). In many cases, this classification is used to assign different functional attributes, such as thermogenesis. We now appreciate that there are different adipocyte precursor cells with distinct lineages and that these lead to adipocyte cell types with discrete and varying functions. This newly gained understanding raises important questions regarding the relationship between adipocyte cell lineage and function, and opens up avenues for therapeutically targeting specific populations of adipocytes as a way to treat metabolic disorders, such as obesity and type 2 diabetes.

White adipose tissue: beyond lipid storage

Classical white adipocytes are unilocular, containing one large lipid droplet serving as a store for triglycerides, with the capacity to expand and contract in response to energy demand [4,5]. WAT depots are distributed throughout the body, with nomenclature differing between species and confusingly, sometimes between individual studies. In rodents, visceral (trunk) depots include the perigonadal (pgWAT), retroperitoneal (rWAT) and mesenteric (mWAT). Subcutaneous adipose depots (scWAT) are divided into the anterior subcutaneous (asWATs), namely the interscapular and axillary WATs, and the inguinal WAT (iWAT) located dorsally, attached to the hindlimb and pelvis [4,6]. These rodent depots and their counterparts in humans are outlined in Figure 1. White adipocytes are also found dispersed in the periphery, with smaller discreet depots including intramuscular [7–9] and dermal [10–12] adipocytes now emerging as important local regulators of tissue function. Depot-specific responses to metabolic alterations caused by diet, age, hormone signalling and disease have been reported, with an increase in visceral adipose mass associated with metabolic disease [13–18]. In contrast, an increase in scWAT correlates with a reduced disease risk [14]. Insights such as these suggest functional differences exist between populations of white adipocytes, influenced by their ability to respond to external stimuli. Thus, an understanding of the origin of individual adipocyte populations within each depot and their respective function will increase our understanding of their contribution to health and disease.

Anatomical location of adipose tissue depots.

Figure 1.
Anatomical location of adipose tissue depots.

The locations of different depots of brown (BAT), subcutaneous and visceral white adipose tissue (WAT) in mice and humans is shown.

Figure 1.
Anatomical location of adipose tissue depots.

The locations of different depots of brown (BAT), subcutaneous and visceral white adipose tissue (WAT) in mice and humans is shown.

A common function of WAT, regardless of anatomical location, is to store and release triglycerides in response to whole body energy demand [13,18–22]. Retrieval of stored lipids is facilitated by a layer of specialised lipid-associated proteins from the perilipin family [23], enabling recruitment of hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and monoacylglycerol lipase (MAGL) to catalyse lipid breakdown [24] 1

1For ease of reading, throughout this review, protein and gene names will be depicted in uppercase regardless of species.

. The existence of perilipin 1 in association with lipid droplets in white adipocytes serves to restrict lipolysis under basal conditions, as well as to create a barrier between otherwise toxic lipid species with surrounding cells [23]. Loss of perilipin 1 leads to increased basal lipolysis, inflammatory cell recruitment denoted by formation of crown-like structures, and ultimately cell death. Several inflammatory stimuli, including tumour necrosis factor α (TNFα) and interleukin 6 (IL6), contribute to increased immune cell infiltration and loss of perilipin 1 in obese individuals, resulting in impaired lipolysis and triglyceride storage in WAT [25,26]. Loss of adipocyte plasticity under these conditions drives peripheral lipid accumulation and contributes to the development of systemic insulin resistance. Preservation of lipid droplet integrity and reduction in pro-inflammatory cytokine release in WAT is therefore critical for the maintenance of normal white adipocyte function, extensively reviewed in [23].

In addition to lipid storage, white adipocytes contribute to whole organism energy homeostasis through the production and secretion of endocrine and paracrine factors, and are themselves sensitive to extracellular signalling [19,27–29]. Insulin, a central regulator of carbon deposition and metabolism, drives glucose uptake in adipocytes and stimulates fatty acid synthesis through increased expression of fatty acid synthase (FAS) [16,17,27]. In cell culture, and in vivo, insulin drives the adipogenic gene programme in adipocyte precursors, through the stimulation of sterol regulatory element-binding protein (SREBP)-1c [30] and up-regulation of the master regulator of adipogenesis peroxisome proliferator-activated receptor gamma (PPARγ) via mammalian target of rapamycin complex 1 (mTORC1) activation [31–33]. Insulin/IGF1 (insulin-like growth factor 1) knockout (KO) mice display significant reduction in adipose tissue mass with defective basal thermogenic capacity [33]. Expression of the insulin receptor (INSR) and intact IGF-1 signalling are therefore critical for the commitment of adipocyte stem cells to adipogenesis and for the maintenance and function of mature adipose tissue [33]. Variations in insulin sensitivity within adipocyte precursor populations is one of several proposed determinants of lineage and cell fate. Deletion of tumour suppressor phosphatase and tensin homologue (PTEN), the negative regulator of insulin/phosphatidylinositol 3-kinase (PI3K) growth stimulating pathways, in a subset of adipocyte precursors, leads to aberrant signalling independent of ligand binding [34,35]. The resulting increase in glucose transport provides a metabolic advantage in targeted cells, driving proliferation, hypertrophy and redistribution of adipose mass. Insulin is just one of several factors implicated in the organisation and selective proliferation of adipocyte precursors. Alterations in adipocyte-derived cytokines (adipokines), including leptin, adiponectin and TNFα are common under obesogenic conditions [16,36–45], causing changes in food intake, impaired satiety response and chronic inflammation [1,46–52]. Infiltration of pro-inflammatory immune cell populations, forming distinctive crown-like structures [53], is a hallmark of obesity and is often associated with onset of insulin resistance, diabetes and loss of metabolic flexibility. The role of WAT in metabolic flexibility is evident, and is reviewed extensively for its hormonal and lipid-storing functions in health and disease. Many studies targeting adipose tissue derived stem cells have benefited from its abundance in mice and humans, and are now beginning to dissect its extraordinary heterogeneity. The following sections will discuss additional adipocyte populations and their contributions to whole organism energy homeostasis.

Brown adipose tissue: UCP-1 mediated thermogenesis and beyond

BAT is highly innervated, highly vascularised and metabolically active [54–58]. Discrete depots are located in the interscapular (iBAT), sub-scapular (sBAT) and cervical (cBAT) regions, and smaller depots have been reported in association with the kidneys and aorta [6,59–63] (shown in Figure 1). Brown-like or ‘beige/brite’ adipocytes, hereafter referred to as beige adipocytes, exhibit many features characteristic of brown adipocytes. Importantly, for the purpose of their classification, beige adipocytes are distinguished by their anatomical location, interspersed in WAT depots. The number of beige adipocytes increases markedly in response to cold-exposure, a phenomenon known as ‘browning’. Most studies indicate that beige adipocytes derive from a white adipocyte precursor stemming mainly from the scWAT depot.

Classical brown adipocytes are hexagonal cells, containing many small lipid droplets (multilocular) and are rich in mitochondria. Brown adipocytes have an extensive endoplasmic reticulum (ER) network that forms contact points with the mitochondria, known as the mitochondria-associated ER membrane (MAM) [64,65]. The primary function of ‘classical’ BAT is widely accepted as non-shivering thermogenesis (NST). This function is enabled by sympathetic innervation, high mitochondrial number and mitochondrial specialisation [66], abundant lipid stores and by the expression of the respiratory chain uncoupling protein 1 (UCP1) [67–70] (see Figure 2). Heat production at the expense of ATP synthesis is in stark contrast with the primary function of white adipocytes, yet both play integral parts in global energy homeostasis, serving as both direct and indirect buffers of nutritional demand and excess.

Thermogenic mechanisms in BAT and WAT.

Figure 2.
Thermogenic mechanisms in BAT and WAT.

Brown adipocyte architecture contributes to thermogenic phenotypes through vascularisation, innervation, multilocular lipid droplets (LD) and high mitochondrial (MT) density. Assembly of mitochondria-organelle networks facilitate substrate utilisation, including the formation of mitochondria-associated ER membrane tethers (MAM) by protein bridges [64,90–96]. (a) Canonical UCP1-mediated thermogenesis via uncoupling of the mitochondrial electron transport chain (ETC), resulting in H+ gradient disturbance and proton leak, dissipating energy as heat. UCP1 activity is stimulated by free fatty acid (FFA) and inhibited by purine nucleotides [65,67,69,97–105]. (b) SERCA/RyR mediated Ca2+ futile cycling in mitochondria. SERCA1 is found in the inner mitochondrial membranes (IMM) of BAT [64,106]. Ca2+ enters the mitochondria via mitochondrial Ca2+ transporters and is pumped into the inner mitochondrial space (IMS) by SERCA1, with concomitant ATP hydrolysis. Ca2+ returns to the matrix via RyR. These cycles are abundant in the ER of brown adipose, heater organs (fish) and skeletal muscle [64,106–113]. A leaky mitochondrial RyR drives increased ATP hydrolysis uncoupled from net Ca2+ transport generating heat. This may also be subject to an unknown uncoupling agent [114]. (c) Non-canonical thermogenesis through creatine futile cycling. ATP generated by the ETC is shuttled into the IMS by the ATP transporter AAC in return for ADP. ATP is then hydrolysed by mitochondrial creatine kinase (mi-CK) to drive creatine phosphorylation to PCr. The reversal, driven by an as yet unidentified enzyme completes the futile cycle [115–118]. (d) Non-canonical thermogenesis by SERCA2b-driven Ca2+ futile cycling on the ER [114,119–121]. See text for more details.

Figure 2.
Thermogenic mechanisms in BAT and WAT.

Brown adipocyte architecture contributes to thermogenic phenotypes through vascularisation, innervation, multilocular lipid droplets (LD) and high mitochondrial (MT) density. Assembly of mitochondria-organelle networks facilitate substrate utilisation, including the formation of mitochondria-associated ER membrane tethers (MAM) by protein bridges [64,90–96]. (a) Canonical UCP1-mediated thermogenesis via uncoupling of the mitochondrial electron transport chain (ETC), resulting in H+ gradient disturbance and proton leak, dissipating energy as heat. UCP1 activity is stimulated by free fatty acid (FFA) and inhibited by purine nucleotides [65,67,69,97–105]. (b) SERCA/RyR mediated Ca2+ futile cycling in mitochondria. SERCA1 is found in the inner mitochondrial membranes (IMM) of BAT [64,106]. Ca2+ enters the mitochondria via mitochondrial Ca2+ transporters and is pumped into the inner mitochondrial space (IMS) by SERCA1, with concomitant ATP hydrolysis. Ca2+ returns to the matrix via RyR. These cycles are abundant in the ER of brown adipose, heater organs (fish) and skeletal muscle [64,106–113]. A leaky mitochondrial RyR drives increased ATP hydrolysis uncoupled from net Ca2+ transport generating heat. This may also be subject to an unknown uncoupling agent [114]. (c) Non-canonical thermogenesis through creatine futile cycling. ATP generated by the ETC is shuttled into the IMS by the ATP transporter AAC in return for ADP. ATP is then hydrolysed by mitochondrial creatine kinase (mi-CK) to drive creatine phosphorylation to PCr. The reversal, driven by an as yet unidentified enzyme completes the futile cycle [115–118]. (d) Non-canonical thermogenesis by SERCA2b-driven Ca2+ futile cycling on the ER [114,119–121]. See text for more details.

Since the discovery of functional BAT in humans [71–73], extensive studies have reviewed its role in the context of health and disease, and as a potential target for the treatment for metabolic disease through the activation of UCP1. Uncoupling of the mitochondrial respiratory chain by UCP1 serves to increase heat production during cold exposure, particularly in hairless neonates, and provides resistance to obesity resulting from overfeeding. Both functions require exquisite sensitivity to extracellular signalling, mediated by dense vascularisation and innervation [74–78]. Perhaps the most well studied of these cascades is the initiation of thermogenesis by adrenergic receptor (AR) signalling. Responses to adrenaline and nor-adrenaline are co-ordinated by ARs, which are members of the G protein-coupled receptor super-family. Brown adipocytes express high levels of β3-ARs which couple to Gs proteins, leading to activation of adenylate cyclase and an increase in intracellular cyclic AMP levels. Cyclic AMP induces gene expression mediated by the transcription factor, cyclic AMP-response element binding protein (CREB) [79]. Brown adipocytes also express α2-ARs, which couple through Gi proteins inhibiting adenylate cyclase, counteracting β3-AR activation of thermogenesis. However, in rodents, β3-AR expression is much higher than α2-AR expression, and so adrenergic-signalling stimulates thermogenesis [80] Stimulation of AR-responsive gene expression is also brought about, at least in part, through p38-mitogen activated protein kinase (p38 MAPK) mediated phosphorylation of activating transcription factor 2 (ATF-2) [81–83], the histone demethylase jumonji domain-containing 1A (JMJD1A) [84,85] and peroxisome proliferator-activated receptor gamma co-activator alpha (PGC1α) [86,87]. PGC1α, once phosphorylated, is free to interact with PPARγ, facilitating the formation of a transcriptional complex with phosphorylated JMJD1A and SWItch/Sucrose Non-Fermentable (SWI/SNF) in adipocyte nuclei, bringing promotor, enhancer and coding regions into proximity, driving beige and brown-specific gene expression [85,88,89].

Extensive literature covers the role and regulation of UCP1-dependent thermogenesis in brown adipose tissue [65,67,69,97–100,122–127]. Based largely in small mammals (rodents), these studies have focused on UCP1 as the principle heat-generating pathway utilised by BAT in response to adrenergic signalling (Figure 2). Ablation of BAT by diphtheria toxin resulted in the onset of obesity and diabetes, coupled with hyperphagia, when mice were housed at ambient temperature. In contrast, global deletion of UCP1 did not recapitulate this phenotype [128], demonstrating that functional BAT, but not UCP1 itself, is required for the prevention of metabolic disease. Supporting this, many studies have characterised UCP1-independent thermogenic mechanisms in both brown and beige adipocytes [67,114–116,119,129–135].

UCP1-Independent thermogenic mechanisms in adipose tissue

The existence of UCP1-independent NST mechanisms is well established, particularly in skeletal muscle [136–138] and, to a lesser extent, in BAT [107–109,139], and provides insight into the origins of endothermy in mammals. Importantly, similar mechanisms have been identified in specialised beige and white adipocytes [115–117], and promotion of these mechanisms leads to improved metabolic health, opening new avenues for the treatment of metabolic disease. Evolutionary evidence suggests that these mechanisms pre-date the emergence of UCP1, a defining feature of BAT, with many species entirely reliant on their existence to facilitate high core body temperatures [136,140]. The hydrolysis of ATP to ADP provides the energy to drive virtually all of the biological processes required to maintain life. However, in addition to providing energy for biological work, the energy from ATP hydrolysis can be converted to heat [108,139,140]. Increased ATP hydrolysis can occur in a futile cycle leading to increased heat production. This mechanism, best described in skeletal muscle, utilises a calcium (Ca2+) futile cycling mechanism involving the ryanodine receptor (RyR) Ca2+ channel and the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) can be used for thermogenesis during cold-stress [136,141]. The sarcoplasmic reticulum (SR), a membranous network in muscle analogous to the endoplasmic reticulum, is responsible for the initiation of muscle contraction and can store Ca2+ in millimolar concentrations. Muscle contraction is initiated by the release of Ca2+into the cytosol by the RyR and relaxation occurs when Ca2+ is actively pumped back into the SR by SERCA. Although this Ca2+ cycling is coupled, a small amount of heat (∼10–25 kcal/mol ATP) is generated with each exchange [106,109,142,143]. In response to cold-stimulus, the binding of sarcolipin (SLN) to SERCA uncouples ATP hydrolysis from Ca2+ transport, at the expense of muscle contraction, generating additional heat. In the absence of UCP1 in BAT, SLN expression is up-regulated in skeletal muscle, enhancing survival rates during cold exposure [144–147]. This compensation is reciprocal, with SLN-KO mice displaying increased UCP1 expression and browning of WAT. Loss of both mechanisms rendered mice extremely cold sensitive during acute exposure, but able to survive if exposed gradually, at the expense of all lipid stores [147]. This implies that the two mechanisms are complementary, and to an extent compensatory, in rodents. Another factor influencing heat production is the rate at which Ca2+ returns to the cytoplasm, through RyRs. The fundamental role of RyRs in Ca2+ driven thermogenesis is highlighted in the context of malignant hyperthermia, in which missense mutations in skeletal muscle RyR1 result in abnormal Ca2+ release in response to ligands, predominantly volatile anaesthetic agents, leading to uncontrolled heat production in skeletal muscle [148]. Although a rare disease, malignant hyperthermia during anaesthesia could often prove fatal, but can now be treated effectively with the RyR inhibitor, dantrolene [149]

In some species, the reliance on muscle-based NST is far greater than in mammals. Ca2+ cycling through SERCA/RyR as a functional thermogenic pathway occurs in the ocular regions of several species of large oceanic, deep diving fish [139,140]. Termed a ‘heater organ’, this structure consists of modified muscle cells that lack proteins required for muscle contraction. Instead, the cells have an extensive SR network with membranous stacks located between mitochondria. This unusual arrangement generates a large surface area of the SR allowing for high level expression of SERCA, together with close proximity to ATP synthesis in the mitochondria. These adaptations enable high rates of Ca2+ cycling to drive thermogenesis. The development of this specialised system enables the fish to maintain eye and brain temperature significantly above the surrounding water temperature, ensuring optimal function in cold environments. In addition, some birds maintain core temperatures in excess of 38°C with some reaching ∼44°C in flight. Studies in hummingbirds have revealed that a futile Ca2+ cycling thermogenic mechanism involving SERCA operates in muscle to facilitate warming following their daily periods of torpor [150].

Though Ca2+ futile cycling is dominant in skeletal muscle, several other substrate fluxes are critical for the maintenance of ATP production [151]. Lipid futile cycling through the lipolysis and re-esterification of free fatty acid (FFA) in white adipose is well documented, in both the presence and absence of UCP1 [152–155]. Data from cultured brown adipocytes suggests these mechanisms are also present in BAT, with little reliance on UCP1 [151]. However, as the maximal thermogenic capacity of these cells in culture is likely diminished, it remains unclear as to whether these mechanisms are efficacious in vivo in response to thermogenic demand. Evidence for both glucose and FFA uptake in BAT in vivo is convincing [63] with administration of a β3-agonist increasing BAT and beige FFA accumulation. However, further work using these improved imaging techniques are required to determine the relative contribution to thermogenesis in the absence of BAT UCP1 [63].

The reliance on UCP1 in BAT for thermogenesis in vivo is likely due to the low expression of ATP synthase (complex V of the electron transport chain) [151,156]. Non-canonical, UCP1-independent thermogenic mechanisms capable of maintaining core body temperature require significant ATP synthesis to drive heat production, limiting the contribution of these pathways in BAT over long periods [97,147,157]. However, many species express functionally inactive UCP1, and several are devoid of UCP1 in their genome [74]. These evolutionary divergences date back as far as the Cretaceous period, and correlate with an increase in body mass and a relative reduction in surface area. Small mammals, such as mice, use UCP1 to facilitate NST during cold periods, at the expense of ATP synthesis otherwise required to build biomass [6,158]. Thus, the study of thermoregulation in mammals has expanded to include mechanisms that whilst historically overshadowed by UCP1, are present and active in brown and beige adipose, outlined in Figure 2. The newly defined role of NST mechanisms in thermogenic adipocytes are perhaps reflective of a shared lineage between brown adipocytes and myocytes; both cell types arise from a lineage distinct from white adipocytes, marked by the myogenic regulatory factor MYF5 [6,34,159–161]. Given the limited efficacy and potential side effects of UCP1 activation in a clinical setting, the possibility of manipulating adipocyte differentiation combined with increasing UCP1-independent thermogenic mechanisms provides potential avenues for therapeutic intervention in key areas of metabolic diseases, including type 2 diabetes and obesity.

The adipocyte lineage: heterogeneity and functionality

As is often the case when attempting to define different cell types, the distinction between adipocyte subtypes is imprecise. The similarities between beige and brown adipocytes raises the question of what is the contribution of their lineage to function. Progenitor pools in white adipose depots are known to give rise to both white and beige adipocytes [6,34,158,162,163], capable of performing both storage and thermogenic functions. Whilst rodents possess distinct brown and beige cell identities, human brown adipocytes exhibit gene expression profiles similar to beige adipocytes in rodents [58,129,164,165]. This suggests human brown adipose may more closely resemble rodent beige adipocytes, emphasising the importance of understanding lineage determination in the development of adipocyte cell type. An important factor to take into account when studying brown and beige thermogenic adipocytes, and particularly when making comparisons between rodents and humans, is the influence of external temperature. Laboratory mice are typically housed at temperatures within the range of 19–23°C, which is ∼10°C below their thermoneutral zone [166]. The thermoneutral zone for a mammal corresponds to the temperature at which the minimal amount of energy is required to maintain body temperature, and for mice this is ∼29°C [167]. This means that most experiments conducted on standard laboratory housed mice are done under sub-thermoneutral conditions. As a consequence, mice respond by increasing thermogenesis, including NST, primarily in BAT. For humans, defining the thermoneutral zone is complicated due to the use of clothing, but under many conditions, humans live within the thermoneutral zone, and so do not require high rates of thermogenesis. Although the effect of external temperature on NST is well appreciated, it is likely that some of the inferences made between human and mouse thermogenic adipocytes are confounded by the temperature at which the studies were performed.

Given the heterogeneity of adipose tissue, the number of discrete depots and the broad functionality of mature adipocytes, it is not surprising that their respective progenitors share the same complexity. Recent studies combining single-cell RNA sequencing and fluorescent imaging techniques have identified a number of new populations of adipose-resident stem cells and ‘pre-adipocytes’ in transition [168–170]. Whether these are each capable of full adipogenesis is an active area of research and is already yielding exciting results. Importantly, many of the populations identified in mice have been found in human adipose tissue, though their contribution to the mature tissue is currently unknown [168,170]. The following section combines what is known so far of the lineages of specialised adipocytes with respect to their functionality, as well as providing an overview of the techniques used to elucidate the hierarchies in adipocyte stem cell niches.

Between brown and white: an adipocyte for all seasons

Although we have significant knowledge of the morphology and function of brown and white adipose tissue, our understanding of their developmental origins are less clear. Identification of beige adipocytes in scWAT depots in response to stimuli associated with proliferation of BAT only serves to reinforce our incomplete view of the situation. Genome-wide surveys of isolated brown adipocytes revealed transcriptional regulators capable of promoting a brown adipose phenotype in pre-adipocytes. Studies later revealed that PR-domain containing 16 (PRDM16) was capable of complete induction of the brown adipose thermogenic programme (e.g. UCP1, PGC1Α, ADRB3 (β3-adrenergic receptor), DIO2 (deiodinase 2)) [160,171–175] and mitochondrial gene expression in cultured mesenchymal stem cells. As a result, in both mice and humans, PRDM16 is regarded as a master regulator of brown adipose identity. PRDM16 is also a powerful repressor of muscle differentiation, an effect that is stabilised by euchromatic histone-lysine N-methyltransferase 1 (EHMT1) [160,172–179]. Indeed, deletion of PRDM16 or EHMT1 reverts cells to a myogenic state, with the formation of myosin heavy chain (MHC) positive myotubes together with expression of skeletal muscle genes and a loss of functional BAT in vivo [160,174,176]. Conversely, ectopic expression of PRDM16 in white adipose tissue drives beige adipocyte formation through interaction with CCAAT-enhancer binding protein β (C/EBPβ) and PPARγ [86,87,89,180]. The interest in PRDM16 as a regulator of adipocyte fate and function has expanded beyond beiging, as genetic overexpression of PRDM16 in white adipocyte depots led to the identification of novel cell types [114,172,174]. At present, it is not known whether these new cell types are expressed in wild type mice, or whether their expression requires specific genetic backgrounds. A summary of adipocyte cell types that have been identified is shown in Table 1.

Table 1
Summary of adipocyte populations, location(s), specialised/stimulating factors and key regulators of cellular fate
Adipocyte (specialised)Known Lineage MarkersSpecialisationKey regulatorsReferences
White (classical) PDGFRα+; PDGFRβ+/−; MYF5+/− (depot-specific); SCA1+; MYH11+; CD34+; CD29+; CD24+; CD31; LIN Adipokine production, lipid storage, endocrine, insulation PPARγ, C/EBPα/β/δ, RXR, CtBP1/2, PRDM16, ZFP423 [4,6,35,181–183
Dermal (dWAT) Camp; Ccl4, classic WAT (see above) Hair cycling, skin wound healing, immune response CAMP [10–12,184–188
Beige/brite PDGFRα+/−; PDGFRβ+/−; SCA1+; MYH11+;CD34+; CD29+; CD24+; CD31; LIN Thermogenesis (UCP1), glucose uptake, mitochondrial respiration, creatine futile cycling PPARγ, PRDM16 EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, ZFP423 EBF2, BMP7 [6,86,97,115,129–131,158, 174,181–183,189–195
Alt. Beige (iWAT) PRDM16++; UCP1−/−; PDGFRα+; SCA1+; MYH11+;CD34+; CD29+; CD24+; CD31; LIN Thermogenesis (Ca2+ futile cycling SERCA2b/RyR2), glucose uptake PRDM16, PPARγ, EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, EBF2, BMP7 [114
g-beige (iWAT) PDGFRα+ SMA+; PAX3+; CD34+; CD29+ MYOD1Lin+ Glucose metabolism, glycolysis (ENO1), UCP1 GABPα [133
Pink (mammary) AP2+; WAP+; ELF5; epithelial Milk production Pregnancy (unknown) [102,196–199
SMART (iWAT) MYF5/6+; PAX7+ Thermogenesis (Ca2+ futile cycling SERCA1/RyR1/3), glucose metabolism, mitochondrial activity AMPK activity [134
BAT MYF5+; EN1+; Pax7+ Lipid storage, Thermogenesis (UCP1 and Ca2+ futile cycling Serca1), glucose metabolism PRDM16/3, PPARγ, EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, EBF2, BMP7, KLF11/15, TLE3 [6,55,58,87,131,174,176, 179,189,194,200–205
Adipocyte (specialised)Known Lineage MarkersSpecialisationKey regulatorsReferences
White (classical) PDGFRα+; PDGFRβ+/−; MYF5+/− (depot-specific); SCA1+; MYH11+; CD34+; CD29+; CD24+; CD31; LIN Adipokine production, lipid storage, endocrine, insulation PPARγ, C/EBPα/β/δ, RXR, CtBP1/2, PRDM16, ZFP423 [4,6,35,181–183
Dermal (dWAT) Camp; Ccl4, classic WAT (see above) Hair cycling, skin wound healing, immune response CAMP [10–12,184–188
Beige/brite PDGFRα+/−; PDGFRβ+/−; SCA1+; MYH11+;CD34+; CD29+; CD24+; CD31; LIN Thermogenesis (UCP1), glucose uptake, mitochondrial respiration, creatine futile cycling PPARγ, PRDM16 EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, ZFP423 EBF2, BMP7 [6,86,97,115,129–131,158, 174,181–183,189–195
Alt. Beige (iWAT) PRDM16++; UCP1−/−; PDGFRα+; SCA1+; MYH11+;CD34+; CD29+; CD24+; CD31; LIN Thermogenesis (Ca2+ futile cycling SERCA2b/RyR2), glucose uptake PRDM16, PPARγ, EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, EBF2, BMP7 [114
g-beige (iWAT) PDGFRα+ SMA+; PAX3+; CD34+; CD29+ MYOD1Lin+ Glucose metabolism, glycolysis (ENO1), UCP1 GABPα [133
Pink (mammary) AP2+; WAP+; ELF5; epithelial Milk production Pregnancy (unknown) [102,196–199
SMART (iWAT) MYF5/6+; PAX7+ Thermogenesis (Ca2+ futile cycling SERCA1/RyR1/3), glucose metabolism, mitochondrial activity AMPK activity [134
BAT MYF5+; EN1+; Pax7+ Lipid storage, Thermogenesis (UCP1 and Ca2+ futile cycling Serca1), glucose metabolism PRDM16/3, PPARγ, EHMT1, PGC1α, C/EBPα/β/δ, ZFP516, EBF2, BMP7, KLF11/15, TLE3 [6,55,58,87,131,174,176, 179,189,194,200–205

The classical beige adipocyte, most notably induced by acute cold exposure, bears a striking resemblance to brown adipocytes, in both morphology and function. These beige adipocytes could occur either by transdifferentiation of mature white adipocytes, or through the proliferation of specific pre-adipocytes from stem cell niches [4,6,15,119,129–132,189,190,196–198,206,207]. Regardless of their origin, the contribution of these cells to adaptive thermogenesis and whole animal physiology has been documented thoroughly, at least in part due to their resemblance to human BAT [97,129,170,191,208,209]. Though new evidence now challenges the singular definition of a beige adipocyte [6,34,210–212], a classical cell signature (platelet-derived growth factor (PDGFR)α+; stem cells antigen 1 (SCA1)+; myosin heavy chain 11 (MYH11)+; CD34+; CD29+; CD24+; CD31-; LIN-) is attributable to both beige and white adipose progenitors [6,162,163]. These are distinct from the adipose endothelial signature (CD34+; CD31+) cells that are required for the formation of vascular endothelium in adipose tissue in vivo [213]. The adipogenic capacity of these vascular cells may yet prove to be of interest, as classical BAT may be in part derived from a CD31+ lineage [214].

As active BAT is low in humans beyond infancy, the potential to induce a brown-like adipocyte in WAT offered new therapeutic possibilities for the treatment of metabolic disease. The use of positron emission tomography (PET) with [18F] fluoro-2-deoxy-glucose (18FDG) in human subjects demonstrated an inverse correlation between BAT mass and body mass index, fasting plasma glucose and adiposity [58,215]. Moreover, BAT mass increased during acute cold stress, demonstrating recruitment of brown adipose progenitors in humans. Refined studies using 18FDG-PET later showed significant uptake in peripheral human BAT depots, including in the posterior subcutaneous region [216–218]. Though largely observational, these studies demonstrated that brown adipocytes are more widespread in humans than originally appreciated, being expressed in both classical BAT and WAT depots. In addition, the studies revealed that in humans brown adipocytes are induced in response to cold exposure, similar to that seen in rodents [97,101,130,170,219].

Despite the extensive work carried out in vitro using primary cells from human WAT, most of the literature surrounding beige adipose in vivo is based on murine models, a bias introduced due primarily to practical limitations than by design. Case studies in cancer cachexia [220–224], severe burn injury [219,225], thyroid carcinoma [226,227] and obesity have reported induction of BAT activation and recruitment of beige adipocytes, but there are no convincing examples of pharmacological induction in humans. Several molecules shown to promote beiging in mice have failed to elicit detectable induction in humans. Irisin, an exercise-induced myokine was shown to have beneficial effects on metabolic parameters associated with browning, including enhanced energy expenditure, lowered blood glucose, and a reduction in adiposity. Circulating irisin levels were correlated with induction of thermogenic genes associated with beiging, including a 5–500-fold induction of UCP1 mRNA [228]. Other studies have since disputed the potential of irisin as a therapeutic strategy, based partly on the finding that circulating irisin levels are increased in obese patients. These discrepancies, reviewed in depth by Crujeiras et al. [229], are as of yet unresolved and warrant further investigation, particularly due to the finding that irisin is also an adipokine and therefore any association with adiposity must be carefully dissociated from fat mass itself [228–232]. Another circulating factor, fibroblast growth factor 21 (FGF21), gained similar traction as a potential browning agent. In addition to its production in the liver, FGF21 has been shown to be secreted from activated brown adipocytes, eliciting a robust increase in UCP1 expression in human neck adipocytes, with lower induction in scWAT [233].

To understand the potential therapeutic relevance of browning of white adipose to human health, there needs to be a distinction between activation of thermogenesis and promotion of substrate utilisation for metabolic work, with heat production simply a by-product. When assessing the contribution of UCP1-mediated thermogenesis in beige adipose, both in mice and in humans, it is important to consider UCP1 protein expression and relative mitochondrial activity, in addition to UCP1 gene expression [234]. The stimulation of UCP1 gene expression by cold exposure in BAT is modest when compared with the ∼100-fold induction seen in WAT [97,131,189,206,235]. However, these differences have little bearing on the actual contribution of the different tissues to total thermogenic capacity [130,132,236]. Rather, they reflect the fact that the level of UCP1 mRNA in WAT is very low under normal experimental conditions. This is because mice are routinely housed at ∼20°C thus the contribution of thermogenesis originating from WAT is low, and UCP1 expression is barely detectable. Following cold-exposure, the fold-induction of UCP1 expression is therefore large, even though the absolute level of UCP1 is low relative to BAT. Examining the contribution of beige cells to whole organism thermogenesis and metabolism is more relevant than focussing on UCP1 induction alone [234,237].

Despite its prominent role in BAT and beige thermogenesis, the loss of UCP1 whilst detrimental in acute cold exposure, is compensated for if gradual cold-acclimatisation is afforded [132,235,238], demonstrating the existence of other, UCP1-independent, thermogenic pathways. A quantitative proteomic study of isolated mitochondria from adipose tissue of cold-expose mice, identified an arginine/creatine metabolic pathway as a beige adipocyte signature [115] . Based on these initial findings, further studies revealed the existence of a creatine-driven futile cycling mechanism contributing to thermogenesis in beige adipocytes [116–118]. The translational significance of these findings is yet to be explored, although cultured human brown adipocytes show sensitivity to creatine-cycling inhibition, and a subset of white adipocytes in abdominal adipose tissue appear to use this mechanism preferentially for thermogenesis [115,116,239–242]. Using a different approach, another study showed that adipose-specific transgenic expression of PRDM16 in UCP1 KO mice led to the enrichment of genes associated with glycolysis, the tricarboxylic acid cycle cycle and strikingly, cardiac muscle contraction, notably the Ca2+ cycling components SERCA2b and RyR2 [114]. Increased expression of SERCA2b and RyR2 is suggestive of the futile Ca2+ cycling mechanism used for thermogenesis in skeletal muscle, described earlier in this article. It is noteworthy, however, that the cardiac isoforms (SERCA2b and RyR2), rather than the skeletal muscle isoforms (SERCA1 and RyR1), were found to be up-regulated. Based on these gene expression changes, the authors showed that inhibition of SERCA by thapsigargin decreased the β-adrenergic-induced increase in respiration [114]. Intriguingly, forced expression of PRDM16 in pig adipocytes, which lack functional UCP1, increased expression of a subset of genes associated with beige adipocytes. Moreover, down-regulation of SERCA2b in these cells reduced basal and β-adrenergic-induced respiration. These findings suggest that a futile Ca2+ cycling mechanism can operate in beige adipocytes, at least in the absence of UCP1.

Whilst extensive efforts have been made to explore the potential for exploiting BAT in treating obesity, to date direct evidence supporting this as a viable approach in humans is lacking. One problem is that activation of thermogenic adipocytes is thought to rely on β-adrenergic signalling, and so would be inherently non-specific. This lack of specificity includes serious negative consequences such as hypertension and increased risk of cardiovascular disease [243]. To identify alternative approaches to inducing thermogenic adipocyte response, Kajimura and colleagues set out to investigate the origin of beige adipocytes in mice lacking β-adrenergic signalling [133]. Consistent with previous findings [244,245]), either pharmacological blockage of β-AR signalling by propranolol, or genetic ablation in β-AR KO mice [246] had little effect on the adaptive thermogenic response to mild cold exposure [133,145,152]. Transcriptomic analysis showed that genes involved in skeletal muscle development, as well as those associated with beiging, were enriched in WAT isolated from β-AR KO mice compared with wild-type mice. Isolated stromal-vascular fraction (SVF) from mice treated with β-blocker contained a subset of cells expressing myogenic differentiation protein 1 (MYOD1) [133]. These cells, capable of forming MHC+ myotubes in culture, were later shown, using MYOD1-CreERT2 GFP-reporter mice, to form UCP1+ beige adipocytes in vivo, termed MYOD1+-derived beige fat [133]. Further analysis of beige adipocytes isolated from the MYOD1+ lineage led to the adoption of the name ‘glycolytic beige’ (g-beige), with significant enrichment of genes involved in glycolysis, glucose and carbohydrate metabolism distinct from both the classical beige and brown adipose signatures [133]. The proliferation of the smooth muscle actin (SMA)+; paired box gene 3 (PAX3)+; PDGFRα+; CD34+; CD29+ progenitor cell was restricted to iWAT, reflective perhaps of the increased heterogeneity and plasticity of this depot, and contributed substantially to whole organism glucose homeostasis. Ablation of MYOD1+-progenitors with diphtheria toxin substantially reduced g-beige formation, leading to reduced glucose uptake and oxygen consumption in WAT and impaired adaptive thermogenesis in response to cold exposure. This study also identified GA-binding protein α (GABPα) as a potent promotor of the differentiation of both MYOD1+ progenitors and C2C12 myoblasts (a mouse skeletal muscle cell line) to an adipocyte lineage. Moreover, GABPα was shown to be required for g-beige formation in vivo [133]. This implies that cold stress can recruit different progenitors, or induce a different differentiation pathway, depending on the level of β-adrenergic signalling. The beneficial effect of g-beige on glucose homeostasis has significant therapeutic potential, but it will be essential to first determine whether g-beige cells are present in humans.

Work from our group identified another type of beige-like adipocyte that we dubbed Skeletal-Muscle like AMP-activated protein kinase (AMPK) Reprogrammed Thermogenic (SMART) cells [134]. Widespread tissue expression of a gain-of-function AMPK mutant in mice led to the induction of SMART cells within the iWAT depot and this was associated with protection against high-fat diet-induced obesity through increased thermogenesis. Importantly, protection against diet-induced obesity was maintained when the mice were housed under thermoneutral conditions (for mice this is ∼30°C), implying that the effect was not reliant on UCP1-dependent thermogenesis. The SMART cells contain small, multilocular lipid droplets and are rich in mitochondria, similar to brown adipocytes. However, SMART cells do not express UCP1, distinguishing them from brown, canonical beige and glycolytic beige adipocytes. In response to a high-fat diet, there was a striking change in gene expression profiles between iWAT isolated from the AMPK gain-of-function mice compared with control mice. Expression of genes associated with striated muscle contraction, including SERCA1a, RyR1 and RyR3, was significantly increased in the gain-of-function mice. These results share obvious parallels with the findings from an earlier study that identified an increase in components of the Ca2+ cycling machinery in WAT of mice expressing PRDM16 in the absence of UCP1 [114]. It is worth noting that the two studies differed in the nature of the isoforms of SERCA and RyR that were up-regulated, with the cardiac isoforms increased in the PRDM16/UCP1 model and the skeletal muscle isoforms increased in the AMPK gain-of-function model.

An important finding in the AMPK gain-of-function model is the apparent bypass of UCP1 as a thermogenic pathway in WAT. Instead, thermogenesis is supported by increased mitochondrial ATP synthesis driving futile Ca2+ cycling mediated by SERCA1/RyR [134]. A previous study reported that pharmacological activation of AMPK promotes beiging in iWAT, with a concomitant increase in UCP1 protein expression, and a modest protection against high-fat diet-induced obesity [247]. In contrast with the genetic gain-of-function model, no evidence was presented to indicate that pharmacological activation of AMPK induced the expression of SMART cells. One possibility for the divergent phenotypes between the two studies could be differences in the degree and/or site of AMPK activation. Relevant to this point, selective expression of the gain-of-function AMPK mutant in mature adipocytes (using adiponectin-Cre) or classical white adipocyte progenitors (using PDGFRα-Cre) did not recapitulate the phenotype seen in the mice crossed with β-actin-Cre (to achieve widespread tissue expression) [134]. These findings suggest that induction of SMART cells requires AMPK activation in a specific, as yet unidentified, progenitor population. Further studies will be needed to identify these progenitor cells and to determine whether pharmacological activation of AMPK in these cells mimics the effect of genetic activation.

The gene signature of SMART cells includes increased expression of three of the four known myogenic regulatory factors (MYF5, MYF6 (also known as MRF4) and myogenin) suggesting that these cells also undergo a myogenic transition. This bears similarity with the g-beige cells, although it seems likely that the SMART cells have a lineage that is distinct from g-beige. This could also account for the difference in isoform expression of SERCA and RyR between SMART cells and UCP1 KO beige adipocytes as described by Ikeda et al. Finally, it is possible that AMPK activation drives the formation of bona fide brown adipocytes, rather than a ‘myogenic beige’, with suppression of UCP1 an independent action leading to the expression of compensatory thermogenic pathways.

As discussed above, several independent studies have identified novel adipocyte subtypes, with diverse functions and all of potential therapeutic benefit. The heterogeneity of adipose tissue, particularly with respect to lineage, is now the subject of intense scrutiny, as it would appear that recruitment of these cells is orchestrated primarily by pre-programmed responses. In vitro studies of these cells in culture provides a valuable approach to characterising their properties, but it will also be important to determine the contribution of the microenvironment in which they reside on their function. Many immune cells are known to modulate adipocyte function, and these processes are often disrupted in pathophysiological conditions [47,178,248,249]. Several reactive stromal populations have been identified which may contribute to adipocyte differentiation both during development and in cancer, providing a key link between tumour development and obesity [49,50]. To evaluate all aspects of adipocyte biology, new technologies, including refined lineage tracing and single-cell RNA sequencing, are being exploited to better characterise precursors and to identify fluctuations potentially linked to disease state [6,34,158,163,168,169,250,251].

Understanding adipocyte lineage in vivo: new technology and future perspectives

Extensive studies using lineage tracing have revealed the complexity and heterogeneity of pathways leading to the generation of adipocytes. The data generated from these studies, though often conflicting, have created a map of adipocyte lineage that is far more intricate than originally appreciated (Figure 3). Several reviews have consolidated these studies, with reference to the model used, the expression patterns observed and the inference of hierarchy within the stem cell niche [6,34,35,158,163,213]. However, the functional significance of lineage remains a key unanswered question. Given that functional differences exist between adipocytes of the same lineage, most notably beige and white, and even between neighbouring cells within a depot [34,158,163], it is unclear as to whether the origin of an adipocyte truly defines its function in vivo. Initial observations suggested that beige adipocytes were derived from transdifferentiation of pre-existing white adipocytes [252,253]. However, other studies indicated that most beige adipocytes stem from differentiation of precursor cells, rather than through transdifferentiation [129,254]. One example of where adipocyte transdifferentiation appears to play an important role is during lactation. The adipose tissue in mammary glands of female mice undergoes significant remodelling, with the generation of milk-producing alveolar cells containing mitochondria and large cytoplasmic lipid droplets, formed without proliferation of a progenitor, but instead derived from pre-existing white adipocytes [197,198].

The heterogeneity and plasticity of adipocyte lineages.

Figure 3.
The heterogeneity and plasticity of adipocyte lineages.

Key metabolic and thermogenic pathways operating in each cell type are shown together with predominant proteins involved in these pathways. Refer to the text for further details.

Figure 3.
The heterogeneity and plasticity of adipocyte lineages.

Key metabolic and thermogenic pathways operating in each cell type are shown together with predominant proteins involved in these pathways. Refer to the text for further details.

The acquisition of a beige phenotype however is less defined, with evidence for transdifferentiation limited to the absence of proliferative events or the retention of a lineage-specific reporter in a morphologically distinct cell. Since many thermogenic adipocytes retain their lineage, as is the case between beige and white, assessment by common lineage markers such as PDGFRα/β does not distinguish a newly recruited cell from a pre-existing one. This is also true of white adipocytes that trace to a MYF5+ lineage, with some also retaining their primitive PAX3+ status in a mosaic-like fashion within one adipose depot [34]. At present no clear functional distinction between MYF5+ white adipocytes and classical PDGFRα+ adipocytes has been observed in the unchallenged state, with thermogenic gene expression similar to MYF5- cells. Though no differential response to prolonged β3-AR stimulation was observed in these depots, deletion of PTEN led to a significant expansion of MYF5+ cells (BAT, retroperitoneal and interscapular WAT), with speculation that increased PI3K signalling, hyper insulin sensitivity and lipid accumulation conferred a metabolic advantage [35,255]. It has been shown that both transdifferentiation and de novo differentiation from precursor cells occurs in response to high fat diet and cold stress. This was demonstrated using a ‘MuralChaser’ lineage tracing system in which zinc finger protein 423 (ZFP423)+/PDGFRβ+ perivascular mural cells [181,182,256,257] were labelled with doxycycline-inducible ZFP423-GFP [181]. De novo adipocyte differentiation from ZFP423-GFP labelled mural cells was observed only after prolonged cold exposure, with the initial browning of the tissue independent of mural cell recruitment. These findings suggest the initial transformation from white to beige adipocytes involves either transdifferentiation of existing white adipocytes, or the recruitment of ZFP423 negative precursor cells. This multi-step process may explain the previously observed ‘harlequin’ patterning [34,211]. In this case, new cells are interspersed with existing cells from different lineages. Understanding the relevance of cell-type specific function and metabolism in these adipocyte lineages could help improve drug specificity and reduce off-target and potentially hazardous side effects, such as those incurred with β3 agonists.

More recently, single-cell RNA sequencing was used to identify distinct cell types in the SVF of both mouse and human adipose tissue [168,251,258–260]. A subset of these cells was found to reside in a new anatomically distinct structure within WAT, termed the reticular interstitium. Present within the reticular interstitium are the stromal cell precursors that are capable of differentiating into white adipocytes in vivo [168,258]. These findings challenge the idea that adipocyte precursors reside solely in the vasculature and peri-vascular regions. Instead, it is possible that adipocyte differentiation can stem from both a stromal (interstitial) mesenchymal dipeptidy peptidase 4 (DPP4)+/Wnt family member 2 (WNT2)+ progenitor [168], and from a PDGFRβ+ cell of peri-vascular origin [162,163,261]. The intermediary cells described by Merrick et al. [168] include the preadipocyte factor-1 (PREF-1)-expressing intercellular adhesion molecule 1 (ICAM1)+ pre-adipocytes, and the alternative CD142+/C-type lectin domain containing 11 (CLEC11)+ cells promoted by transforming growth factor β (TGFβ)–inhibition of ICAM1+ cells. Subsequently, additional populations of adipocytes were identified in humans with several clusters positively correlated with high mitochondrial content, oxidative metabolism and inversely correlated with disease state [258]. Though the attribution of function to these newly established hierarchies is not yet established, several inferences can be made, based on pre-existing understanding of adipose derived stem cell proliferation in vivo. Some of these links are shown in Figure 4 and have been reviewed recently [251].

Contribution of known stem cell niches to mature adipocyte development.

Figure 4.
Contribution of known stem cell niches to mature adipocyte development.

Adipose-stem cell (ASC) populations identified by single-cell RNA sequencing are shown with respect to proposed nomenclature and existing hierarchies [168,251,258,261–265]. ASC1, known formerly as Adipose Progenitor Cells (APCs) and committed pre-adipocytes, have been identified in all single-cell RNA sequencing studies reported, and give rise to mature adipocytes in vivo. They are further classified as ASC1a and ASC1b, with respect to their progenitor population. ASC1a, also known as APC and ICAM1/PREF-1 expressing pre-adipocytes are prevalent in most differentiated tissue, irrespective of depot. They encompass both PDGFRβ+ mural cells and PDGFRα+/PDGFRβ precursors, commonly associated with classical adipogenesis and are SCA1+. ASC1b, previously identified as CD142+/AREG adipocyte precursors are a distinct population, arising from a second master progenitor, ASC2. ASC2/DPP4+/FIP+ cells are of stromal origin, residing in the reticular interstitium (RI) of iWAT and mesothelium of eWAT). ASC2 cells give rise to both ASC1a and 1b populations, with TGFβ a potent lineage determinant between these cell fates. Immune cell populations contribute to the differentiation of ASC populations, with CD9+ macrophages expressing SPP1 and TREM2 found in crown-like structures surrounding mature adipocytes [251,265]. Functional differences identified between these populations suggest that all are adipogenic, with stimulus-specific recruitment under inflammatory and adrenergic stimuli.

Figure 4.
Contribution of known stem cell niches to mature adipocyte development.

Adipose-stem cell (ASC) populations identified by single-cell RNA sequencing are shown with respect to proposed nomenclature and existing hierarchies [168,251,258,261–265]. ASC1, known formerly as Adipose Progenitor Cells (APCs) and committed pre-adipocytes, have been identified in all single-cell RNA sequencing studies reported, and give rise to mature adipocytes in vivo. They are further classified as ASC1a and ASC1b, with respect to their progenitor population. ASC1a, also known as APC and ICAM1/PREF-1 expressing pre-adipocytes are prevalent in most differentiated tissue, irrespective of depot. They encompass both PDGFRβ+ mural cells and PDGFRα+/PDGFRβ precursors, commonly associated with classical adipogenesis and are SCA1+. ASC1b, previously identified as CD142+/AREG adipocyte precursors are a distinct population, arising from a second master progenitor, ASC2. ASC2/DPP4+/FIP+ cells are of stromal origin, residing in the reticular interstitium (RI) of iWAT and mesothelium of eWAT). ASC2 cells give rise to both ASC1a and 1b populations, with TGFβ a potent lineage determinant between these cell fates. Immune cell populations contribute to the differentiation of ASC populations, with CD9+ macrophages expressing SPP1 and TREM2 found in crown-like structures surrounding mature adipocytes [251,265]. Functional differences identified between these populations suggest that all are adipogenic, with stimulus-specific recruitment under inflammatory and adrenergic stimuli.

Future perspectives

In this article we have explored the interconversion of white and brown adipocytes and the basic functional consequences of adipocyte lineage. From the first identification of brown and beige adipose, researchers have been fascinated by the heterogeneity and plasticity of this abundant source of stem cells, with many applications beyond the treatment of metabolic disease. Easily accessible and with a lower rejection rate, adipose derived stem cells have been investigated for the treatment of ischemia [266] and stroke [267], to repair cartilage [268–270] and to generate stem cells for spinal injury and neurodegenerative disorder transplant therapy, through the production of neuron- and glial-like cells [271–273]. Whilst our understanding of adipocyte function has advanced significantly, we are only just beginning to explore the links between developmental origins and plasticity with respect to therapeutic potential. Future studies will undoubtedly build upon the large data-sets generated by -omics and single-cell techniques using targeted reporter systems, better-informed cell culture systems and refined imaging strategies to unpick the complex and diverse mechanisms governing adipose development. Based on these studies, we expect to see exciting new therapeutic interventions emerge based not just on small molecules, but perhaps on adipocyte stem cell therapy, for the treatment of metabolic disease.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Open Access

Open access for this article was enabled by the participation of Imperial College London in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.

Acknowledgements

Work in the authors’ laboratory was funded by the Medical Research Council [MC-A654-5QB10] and through a post-doctoral fellowship from AstraZeneca (A.E.P.).

Abbreviations

     
  • AMPK

    AMP-activated protein kinase

  •  
  • AR

    adrenergic receptor

  •  
  • BAT

    brown adipose tissue

  •  
  • ER

    endoplasmic reticulum

  •  
  • FFA

    free fatty acid

  •  
  • FDG

    fluoro-2-deoxy glucose

  •  
  • iWAT

    inguinal white adipose tissue

  •  
  • KO

    knockout

  •  
  • MAM

    mitochondria-associated endoplasmic reticulum membrane

  •  
  • MYOD1

    myogenic differentiation protein 1

  •  
  • MYF

    myogenic regulatory factor

  •  
  • NST

    non-shivering thermogenesis

  •  
  • PET

    positron emission tomography

  •  
  • PDGFR

    platelet-derived growth factor receptor

  •  
  • PRDM16

    PR-domain containing 16

  •  
  • RyR

    ryanodine receptor

  •  
  • scWAT

    subcutaneous white adipose tissue

  •  
  • SERCA

    sarco/endoplasmic reticulum Ca2+ ATPase

  •  
  • SLN

    sarcolipin

  •  
  • SMART

    skeletal muscle-like AMP-activated protein kinase reprogrammed thermogenic

  •  
  • SR

    sarcoplasmic reticulum

  •  
  • SVF

    stromal-vascular fraction

  •  
  • UCP1

    uncoupling protein 1

  •  
  • WAT

    white adipose tissue

  •  
  • ZFP423

    zinc finger protein 423

References

References
1
Smith
,
R.L.
,
Soeters
,
M.R.
,
Wust
,
R.C.I.
and
Houtkooper
,
R.H.
(
2018
)
Metabolic flexibility as an adaptation to energy resources and requirements in health and disease
.
Endocr. Rev.
39
,
489
517
2
Goodpaster
,
B.H.
and
Sparks
,
L.M.
(
2017
)
Metabolic flexibility in health and disease
.
Cell Metab.
25
,
1027
1036
3
Muoio
,
D.M.
(
2014
)
Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock
.
Cell
159
,
1253
1262
4
Cinti
,
S.
(
2012
)
The adipose organ at a glance
.
Dis. Model Mech.
5
,
588
594
5
Faust
,
I.M.
,
Johnson
,
P.R.
,
Stern
,
J.S.
and
Hirsch
,
J.
(
1978
)
Diet-induced adipocyte number increase in adult rats: a new model of obesity
.
Am. J. Physiol.
235
,
E279
E286
6
Sanchez-Gurmaches
,
J.
and
Guertin
,
D.A.
(
2014
)
Adipocyte lineages: tracing back the origins of fat
.
Biochim. Biophys. Acta
1842
,
340
351
7
Begaye
,
L.
and
Simcox
,
J.A.
(
2019
)
Intramuscular adipocytes: a buried adipose tissue depot deserving more exploration
.
J. Lipid Res.
60
,
753
754
8
Hausman
,
G.J.
,
Basu
,
U.
,
Du
,
M.
,
Fernyhough-Culver
,
M.
and
Dodson
,
M.V.
(
2014
)
Intermuscular and intramuscular adipose tissues: bad vs. good adipose tissues
.
Adipocyte
3
,
242
255
9
Ogawa
,
M.
,
Lester
,
R.
,
Akima
,
H.
and
Gorgey
,
A.S.
(
2017
)
Quantification of intermuscular and intramuscular adipose tissue using magnetic resonance imaging after neurodegenerative disorders
.
Neural Regen. Res.
12
,
2100
2105
10
Kruglikov
,
I.L.
and
Scherer
,
P.E.
(
2016
)
Dermal adipocytes and hair cycling: is spatial heterogeneity a characteristic feature of the dermal adipose tissue depot?
Exp. Dermatol.
25
,
258
262
11
Kruglikov
,
I.L.
and
Scherer
,
P.E.
(
2016
)
Dermal adipocytes: from irrelevance to metabolic targets?
Trends Endocrinol. Metab.
27
,
1
10
12
Zhang
,
Z.
,
Shao
,
M.
,
Hepler
,
C.
,
Zi
,
Z.
,
Zhao
,
S.
,
An
,
Y.A.
et al (
2019
)
Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice
.
J. Clin. Invest.
129
,
5327
5342
13
Hoffstedt
,
J.
,
Arner
,
P.
,
Hellers
,
G.
and
Lonnqvist
,
F.
(
1997
)
Variation in adrenergic regulation of lipolysis between omental and subcutaneous adipocytes from obese and non-obese men
.
J. Lipid Res.
38
,
795
804
PMID:
[PubMed]
14
Wajchenberg
,
B.L.
(
2000
)
Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome
.
Endocr. Rev.
21
,
697
738
15
Cinti
,
S.
(
2002
)
Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ
.
J. Endocrinol. Invest.
25
,
823
835
16
Wajchenberg
,
B.L.
,
Giannella-Neto
,
D.
,
da Silva
,
M.E.
and
Santos
,
R.F.
(
2002
)
Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome
.
Horm. Metab. Res.
34
,
616
621
17
Fisher
,
R.M.
,
Thorne
,
A.
,
Hamsten
,
A.
and
Arner
,
P.
(
2002
)
Fatty acid binding protein expression in different human adipose tissue depots in relation to rates of lipolysis and insulin concentration in obese individuals
.
Mol. Cell. Biochem.
239
,
95
100
18
Lundgren
,
M.
,
Buren
,
J.
,
Lindgren
,
P.
,
Myrnas
,
T.
,
Ruge
,
T.
and
Eriksson
,
J.W.
(
2008
)
Sex- and depot-specific lipolysis regulation in human adipocytes: interplay between adrenergic stimulation and glucocorticoids
.
Horm. Metab. Res.
40
,
854
860
19
Belfrage
,
P.
,
Fredrikson
,
G.
,
Nilsson
,
N.O.
and
Stralfors
,
P.
(
1980
)
Regulation of adipose tissue lipolysis: phosphorylation of hormones sensitive lipase in intact rat adipocytes
.
FEBS Lett.
111
,
120
124
20
Schimmel
,
R.J.
,
McMahon
,
K.K.
and
Serio
,
R.
(
1981
)
Interactions between alpha-adrenergic agents, prostaglandin E1, nicotinic acid, and adenosine in regulation of lipolysis in hamsters epididymal adipocytes
.
Mol. Pharmacol.
19
,
248
255
PMID:
[PubMed]
21
Atgie
,
C.
,
D'Allaire
,
F.
and
Bukowiecki
,
L.J.
(
1997
)
Role of beta1- and beta3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes
.
Am. J Physiol.
273
,
C1136
C1142
22
Reynisdottir
,
S.
,
Langin
,
D.
,
Carlstrom
,
K.
,
Holm
,
C.
,
Rossner
,
S.
and
Arner
,
P.
(
1995
)
Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity
.
Clin. Sci. (Lond)
89
,
421
429
23
Sztalryd
,
C.
and
Brasaemle
,
D.L.
(
2017
)
The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis
.
Biochim. Biophys. Acta Mol. Cell. Biol. Lipids
1862
,
1221
1232
24
Duncan
,
R.E.
,
Ahmadian
,
M.
,
Jaworski
,
K.
,
Sarkadi-Nagy
,
E.
and
Sul
,
H.S.
(
2007
)
Regulation of lipolysis in adipocytes
.
Annu. Rev. Nutr.
27
,
79
101
25
Ogasawara
,
J.
,
Nomura
,
S.
,
Rahman
,
N.
,
Sakurai
,
T.
,
Kizaki
,
T.
,
Izawa
,
T.
et al (
2010
)
Hormone-sensitive lipase is critical mediators of acute exercise-induced regulation of lipolysis in rat adipocytes
.
Biochem. Biophys. Res. Commun.
400
,
134
139
26
Ju
,
L.
,
Han
,
J.
,
Zhang
,
X.
,
Deng
,
Y.
,
Yan
,
H.
,
Wang
,
C.
et al (
2019
)
Obesity-associated inflammation triggers an autophagy-lysosomal response in adipocytes and causes degradation of perilipin 1
.
Cell Death Dis.
10
,
121
27
Nilsson
,
N.O.
,
Stralfors
,
P.
,
Fredrikson
,
G.
and
Belfrage
,
P.
(
1980
)
Regulation of adipose tissue lipolysis: effects of noradrenaline and insulin on phosphorylation of hormone-sensitive lipase and on lipolysis in intact rat adipocytes
.
FEBS Lett.
111
,
125
130
28
Larsen
,
T.S.
and
Nilssen
,
K.J.
(
1985
)
On the hormonal regulation of lipolysis in isolated reindeer adipocytes
.
Acta Physiol. Scand.
125
,
547
552
29
Holm
,
C.
,
Osterlund
,
T.
,
Laurell
,
H.
and
Contreras
,
J.A.
(
2000
)
Molecular mechanisms regulating hormone-sensitive lipase and lipolysis
.
Annu. Rev. Nutr.
20
,
365
393
30
Le Lay
,
S.
,
Lefrere
,
I.
,
Trautwein
,
C.
,
Dugail
,
I.
and
Krief
,
S.
(
2002
)
Insulin and sterol-regulatory element-binding protein-1c (SREBP-1C) regulation of gene expression in 3T3-L1 adipocytes. Identification of CCAAT/enhancer-binding protein beta as an SREBP-1C target.
J. Biol. Chem.
277
,
35625
35634
31
Kim
,
J.E.
and
Chen
,
J.
(
2004
)
Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis
.
Diabetes
53
,
2748
2756
32
Laplante
,
M.
,
Horvat
,
S.
,
Festuccia
,
W.T.
,
Birsoy
,
K.
,
Prevorsek
,
Z.
,
Efeyan
,
A.
et al (
2012
)
DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity
.
Cell Metab.
16
,
202
212
33
Boucher
,
J.
,
Mori
,
M.A.
,
Lee
,
K.Y.
,
Smyth
,
G.
,
Liew
,
C.W.
,
Macotela
,
Y.
et al (
2012
)
Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling
.
Nat. Commun.
3
,
902
34
Sanchez-Gurmaches
,
J.
and
Guertin
,
D.A.
(
2014
)
Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed
.
Nat. Commun.
5
,
4099
35
Sanchez-Gurmaches
,
J.
,
Hung
,
C.M.
,
Sparks
,
C.A.
,
Tang
,
Y.
,
Li
,
H.
and
Guertin
,
D.A.
(
2012
)
PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors
.
Cell Metab.
16
,
348
362
36
Montague
,
C.T.
,
Farooqi
,
I.S.
,
Whitehead
,
J.P.
,
Soos
,
M.A.
,
Rau
,
H.
,
Wareham
,
N.J.
et al (
1997
)
Congenital leptin deficiency is associated with severe early-onset obesity in humans
.
Nature
387
,
903
908
37
Considine
,
R.V.
,
Considine
,
E.L.
,
Williams
,
C.J.
,
Hyde
,
T.M.
and
Caro
,
J.F.
(
1996
)
The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations
.
Diabetes
45
,
992
994
38
Varela
,
L.
and
Horvath
,
T.L.
(
2012
)
Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis
.
EMBO Rep.
13
,
1079
1086
39
Beck
,
B.
(
2000
)
Neuropeptides and obesity
.
Nutrition
16
,
916
923
40
Levin
,
B.E.
,
Dunn-Meynell
,
A.A.
and
Banks
,
W.A.
(
2004
)
Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
286
,
R143
R150
41
Ahima
,
R.S.
(
2008
)
Revisiting leptin's role in obesity and weight loss
.
J. Clin. Invest.
118
,
2380
2383
42
Bates
,
S.H.
,
Stearns
,
W.H.
,
Dundon
,
T.A.
,
Schubert
,
M.
,
Tso
,
A.W.
,
Wang
,
Y.
et al (
2003
)
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
.
Nature
421
,
856
859
43
Dridi
,
S.
and
Taouis
,
M.
(
2009
)
Adiponectin and energy homeostasis: consensus and controversy
.
J. Nutr. Biochem.
20
,
831
839
44
Achari
,
A.E.
and
Jain
,
S.K.
(
2017
)
Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction
.
Int. J. Mol. Sci.
18
,
1321
45
Hu
,
E.
,
Liang
,
P.
and
Spiegelman
,
B.M.
(
1996
)
Adipoq is a novel adipose-specific gene dysregulated in obesity
.
J. Biol. Chem.
271
,
10697
10703
46
Alkhouri
,
N.
,
Dixon
,
L.J.
and
Feldstein
,
A.E.
(
2009
)
Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal
.
Expert. Rev. Gastroenterol. Hepatol.
3
,
445
451
47
Sakamoto
,
T.
,
Nitta
,
T.
,
Maruno
,
K.
,
Yeh
,
Y.S.
,
Kuwata
,
H.
,
Tomita
,
K.
et al (
2016
)
Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice
.
Am. J. Physiol. Endocrinol. Metab.
310
,
E676
E687
48
Laclaustra
,
M.
,
Corella
,
D.
and
Ordovas
,
J.M.
(
2007
)
Metabolic syndrome pathophysiology: the role of adipose tissue
.
Nutr. Metab. Cardiovasc. Dis.
17
,
125
139
49
Quail
,
D.F.
and
Dannenberg
,
A.J.
(
2019
)
The obese adipose tissue microenvironment in cancer development and progression
.
Nat. Rev. Endocrinol.
15
,
139
154
50
Himbert
,
C.
,
Delphan
,
M.
,
Scherer
,
D.
,
Bowers
,
L.W.
,
Hursting
,
S.
and
Ulrich
,
C.M.
(
2017
)
Signals from the adipose microenvironment and the obesity-cancer link-a systematic review
.
Cancer Prev. Res. (Phila)
10
,
494
506
51
Cawthorn
,
W.P.
and
Sethi
,
J.K.
(
2008
)
TNF-α and adipocyte biology
.
FEBS Lett.
582
,
117
131
52
Kim
,
K.Y.
,
Kim
,
H.Y.
,
Kim
,
J.H.
,
Lee
,
C.H.
,
Kim
,
D.H.
,
Lee
,
Y.H.
et al (
2006
)
Tumor necrosis factor-alpha and interleukin-1beta increases CTRP1 expression in adipose tissue
.
FEBS Lett.
580
,
3953
3960
53
Murano
,
I.
,
Barbatelli
,
G.
,
Parisani
,
V.
,
Latini
,
C.
,
Muzzonigro
,
G.
,
Castellucci
,
M.
et al (
2008
)
Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice
.
J. Lipid Res.
49
,
1562
1568
54
Foster
,
D.O.
and
Frydman
,
M.L.
(
1979
)
Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis
.
Can. J. Physiol. Pharmacol.
57
,
257
270
55
Nicholls
,
D.G.
and
Locke
,
R.M.
(
1984
)
Thermogenic mechanisms in brown fat
.
Physiol. Rev.
64
,
1
64
56
Young
,
P.
,
Arch
,
J.R.
and
Ashwell
,
M.
(
1984
)
Brown adipose tissue in the parametrial fat pad of the mouse
.
FEBS Lett.
167
,
10
14
57
Cousin
,
B.
,
Cinti
,
S.
,
Morroni
,
M.
,
Raimbault
,
S.
,
Ricquier
,
D.
,
Penicaud
,
L.
et al (
1992
)
Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization
.
J. Cell Sci.
103
,
931
942
PMID:
[PubMed]
58
Virtanen
,
K.A.
,
Lidell
,
M.E.
,
Orava
,
J.
,
Heglind
,
M.
,
Westergren
,
R.
,
Niemi
,
T.
et al (
2009
)
Functional brown adipose tissue in healthy adults
.
N. Engl. J. Med.
360
,
1518
1525
59
Wei
,
H.
,
Chiba
,
S.
,
Moriwaki
,
C.
,
Kitamura
,
H.
,
Ina
,
K.
,
Aosa
,
T.
et al (
2015
)
A clinical approach to brown adipose tissue in the para-aortic area of the human thorax
.
PLoS One
10
,
e0122594
60
Sacks
,
H.
and
Symonds
,
M.E.
(
2013
)
Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes
.
Diabetes
62
,
1783
1790
61
Gao
,
Y.J.
(
2007
)
Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction
.
Curr. Pharm. Des.
13
,
2185
2192
62
Wu
,
N.N.
,
Zhang
,
C.H.
,
Lee
,
H.J.
,
Ma
,
Y.
,
Wang
,
X.
,
Ma
,
X.J.
et al (
2016
)
Brown adipogenic potential of brown adipocytes and peri-renal adipocytes from human embryo
.
Sci. Rep.
6
,
39193
63
Zhang
,
F.
,
Hao
,
G.
,
Shao
,
M.
,
Nham
,
K.
,
An
,
Y.
,
Wang
,
Q.
et al (
2018
)
An adipose tissue atlas: an image-guided identification of human-like BAT and beige depots in rodents
.
Cell Metab.
27
,
252
262.e253
64
de Meis
,
L.
,
Ketzer
,
L.A.
,
da Costa
,
R.M.
,
de Andrade
,
I.R.
and
Benchimol
,
M.
(
2010
)
Fusion of the endoplasmic reticulum and mitochondrial outer membrane in rats brown adipose tissue: activation of thermogenesis by Ca2+
.
PLoS One
5
,
e9439
65
Cohen
,
P.
and
Spiegelman
,
B.M.
(
2015
)
Brown and beige fat: molecular parts of a thermogenic machine
.
Diabetes
64
,
2346
2351
66
Forner
,
F.
,
Kumar
,
C.
,
Luber
,
C.A.
,
Fromme
,
T.
,
Klingenspor
,
M.
and
Mann
,
M.
(
2009
)
Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions
.
Cell Metab.
10
,
324
335
67
Shabalina
,
I.G.
,
Petrovic
,
N.
,
de Jong
,
J.M.
,
Kalinovich
,
A.V.
,
Cannon
,
B.
and
Nedergaard
,
J.
(
2013
)
UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic
.
Cell Rep.
5
,
1196
1203
68
Ricquier
,
D.
(
1998
)
Neonatal brown adipose tissue, UCP1 and the novel uncoupling proteins
.
Biochem. Soc. Trans.
26
,
120
123
69
Nicholls
,
D.G.
(
2001
)
A history of UCP1
.
Biochem. Soc. Trans.
29
,
751
755
70
Rosen
,
E.D.
and
Spiegelman
,
B.M.
(
2014
)
What we talk about when we talk about fat
.
Cell
156
,
20
44
71
Borga
,
M.
,
Virtanen
,
K.A.
,
Romu
,
T.
,
Leinhard
,
O.D.
,
Persson
,
A.
,
Nuutila
,
P.
et al (
2014
)
Brown adipose tissue in humans: detection and functional analysis using PET (positron emission tomography), MRI (magnetic resonance imaging), and DECT (dual energy computed tomography)
.
Methods Enzymol.
537
,
141
159
72
Gonzalez-Barroso
,
D.M.
,
Ricquier
,
M.
,
and Cassard-Doulcier
,
D.
and
M
,
A.
(
2000
)
The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research
.
Obes. Rev.
1
,
61
72
73
Zingaretti
,
M.C.
,
Crosta
,
F.
,
Vitali
,
A.
,
Guerrieri
,
M.
,
Frontini
,
A.
,
Cannon
,
B.
et al (
2009
)
The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue
.
FASEB J.
23
,
3113
3120
74
Klingenspor
,
M.
,
Fromme
,
T.
,
Hughes
, Jr,
D.A.
,
Manzke
,
L.
,
Polymeropoulos
,
E.
,
Riemann
,
T.
et al (
2008
)
An ancient look at UCP1
.
Biochim. Biophys. Acta
1777
,
637
641
75
Festuccia
,
W.T.
,
Blanchard
,
P.G.
,
Richard
,
D.
and
Deshaies
,
Y.
(
2010
)
Basal adrenergic tone is required for maximal stimulation of rat brown adipose tissue UCP1 expression by chronic PPAR-gamma activation
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
299
,
R159
R167
76
Klingenspor
,
M.
(
2003
)
Cold-induced recruitment of brown adipose tissue thermogenesis
.
Exp. Physiol.
88
,
141
148
77
Zeng
,
X.
,
Ye
,
M.
,
Resch
,
J.M.
,
Jedrychowski
,
M.P.
,
Hu
,
B.
,
Lowell
,
B.B.
et al (
2019
)
Innervation of thermogenic adipose tissue via a calsyntenin 3beta-S100b axis
.
Nature
569
,
229
235
78
Scarpace
,
P.J.
and
Matheny
,
M.
(
1998
)
Leptin induction of UCP1 gene expression is dependent on sympathetic innervation
.
Am. J. Physiol.
275
,
E259
E264
79
Rosen
,
E.D.
and
Spiegelman
,
B.M.
(
2000
)
Molecular regulation of adipogenesis
.
Annu. Rev. Cell Dev. Biol.
16
,
145
171
80
Braun
,
K.
,
Oeckl
,
J.
,
Westermeier
,
J.
,
Li
,
Y.
and
Klingenspor
,
M.
(
2018
)
Non-adrenergic control of lipolysis and thermogenesis in adipose tissues
.
J. Exp. Biol
,
221
,
jeb165381
81
Cao
,
W.
,
Daniel
,
K.W.
,
Robidoux
,
J.
,
Puigserver
,
P.
,
Medvedev
,
A.V.
,
Bai
,
X.
et al (
2004
)
P38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene
.
Mol. Cell. Biol.
24
,
3057
3067
82
Cao
,
W.
,
Medvedev
,
A.V.
,
Daniel
,
K.W.
and
Collins
,
S.
(
2001
)
beta-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction=of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase
.
J. Biol. Chem.
276
,
27077
27082
83
Xue
,
B.
,
Coulter
,
A.
,
Rim
,
J.S.
,
Koza
,
R.A.
and
Kozak
,
L.P.
(
2005
)
Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots
.
Mol. Cell. Biol.
25
,
8311
8322
84
Abe
,
Y.
,
Fujiwara
,
Y.
,
Takahashi
,
H.
,
Matsumura
,
Y.
,
Sawada
,
T.
,
Jiang
,
S.
et al (
2018
)
Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch
.
Nat. Commun.
9
,
1566
85
Abe
,
Y.
,
Rozqie
,
R.
,
Matsumura
,
Y.
,
Kawamura
,
T.
,
Nakaki
,
R.
,
Tsurutani
,
Y.
et al (
2015
)
JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis
.
Nat. Commun.
6
,
7052
86
Inagaki
,
T.
,
Sakai
,
J.
and
Kajimura
,
S.
(
2016
)
Transcriptional and epigenetic control of brown and beige adipose cell fate and function
.
Nat. Rev. Mol. Cell Biol.
17
,
480
495
87
Kajimura
,
S.
,
Seale
,
P.
and
Spiegelman
,
B.M.
(
2010
)
Transcriptional control of brown fat development
.
Cell Metab.
11
,
257
262
88
Seale
,
P.
(
2015
)
Transcriptional regulatory circuits controlling brown fat development and activation
.
Diabetes
64
,
2369
2375
89
Seale
,
P.
(
2010
)
Transcriptional control of brown adipocyte development and thermogenesis
.
Int. J. Obes. (Lond)
34
,
S17
S22
90
Annunziata
,
I.
,
Patterson
,
A.
and
d'Azzo
,
A.
(
2013
)
Mitochondria-associated ER membranes (MAMs) and glycosphingolipid enriched microdomains (GEMs): isolation from mouse brain
.
J. Vis. Exp.
e50215
91
Honrath
,
B.
,
Culmsee
,
C.
and
Dolga
,
A.M.
(
2018
)
One protein, different cell fate: the differential outcome of depleting GRP75 during oxidative stress in neurons
.
Cell Death Dis.
9
,
32
92
Thoudam
,
T.
,
Ha
,
C.M.
,
Leem
,
J.
,
Chanda
,
D.
,
Park
,
J.S.
,
Kim
,
H.J.
et al (
2019
)
PDK4 augments ER-mitochondria contact to dampen skeletal muscle insulin signaling during obesity
.
Diabetes
68
,
571
586
93
Zhou
,
H.
,
Wang
,
S.
,
Hu
,
S.
,
Chen
,
Y.
and
Ren
,
J.
(
2018
)
ER-mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective
.
Front. Physiol.
9
,
755
94
Gomez-Suaga
,
P.
,
Bravo-San Pedro
,
J.M.
,
Gonzalez-Polo
,
R.A.
,
Fuentes
,
J.M.
and
Niso-Santano
,
M.
(
2018
)
ER-mitochondria signaling in Parkinson's disease
.
Cell Death Dis.
9
,
337
95
Gomez-Suaga
,
P.
,
Paillusson
,
S.
and
Miller
,
C.C.J.
(
2017
)
ER-mitochondria signaling regulates autophagy
.
Autophagy
13
,
1250
1251
96
Tubbs
,
E.
and
Rieusset
,
J.
(
2017
)
Metabolic signaling functions of ER-mitochondria contact sites: role in metabolic diseases
.
J. Mol. Endocrinol.
58
,
R87
R106
97
Ikeda
,
K.
,
Maretich
,
P.
and
Kajimura
,
S.
(
2018
)
The common and distinct features of brown and beige adipocytes
.
Trends Endocrinol. Metab.
29
,
191
200
98
Nicholls
,
D.G.
and
Rial
,
E.
(
1999
)
A history of the first uncoupling protein, UCP1
.
J. Bioenerg. Biomembr.
31
,
399
406
99
Klingenberg
,
M.
(
2017
)
UCP1 - a sophisticated energy valve
.
Biochimie
134
,
19
27
100
Bertholet
,
A.M.
and
Kirichok
,
Y.
(
2017
)
UCP1: a transporter for H(+) and fatty acid anions
.
Biochimie
134
,
28
34
101
Bartesaghi
,
S.
,
Hallen
,
S.
,
Huang
,
L.
,
Svensson
,
P.A.
,
Momo
,
R.A.
,
Wallin
,
S.
et al (
2015
)
Thermogenic activity of UCP1 in human white fat-derived beige adipocytes
.
Mol. Endocrinol.
29
,
130
139
102
Cinti
,
S.
(
2017
)
UCP1 protein: the molecular hub of adipose organ plasticity
.
Biochimie
134
,
71
76
103
Hughes
,
D.A.
,
Jastroch
,
M.
,
Stoneking
,
M.
and
Klingenspor
,
M.
(
2009
)
Molecular evolution of UCP1 and the evolutionary history of mammalian non-shivering thermogenesis
.
BMC Evol. Biol.
9
,
4
104
Rodriguez-Sanchez
,
L.
and
Rial
,
E.
(
2017
)
The distinct bioenergetic properties of the human UCP1
.
Biochimie
134
,
51
55
105
Divakaruni
,
A.S.
,
Humphrey
,
D.M.
and
Brand
,
M.D.
(
2012
)
Fatty acids change the conformation of uncoupling protein 1 (UCP1)
.
J. Biol. Chem.
287
,
36845
36853
106
Arruda
,
A.P.
,
Nigro
,
M.
,
Oliveira
,
G.M.
and
de Meis
,
L.
(
2007
)
Thermogenic activity of Ca2+-ATPase from skeletal muscle heavy sarcoplasmic reticulum: the role of ryanodine Ca2+ channel
.
Biochim. Biophys. Acta
1768
,
1498
1505
107
de Meis
,
L.
(
2003
)
Brown adipose tissue Ca2+-ATPase: uncoupled ATP hydrolysis and thermogenic activity
.
J. Biol. Chem.
278
,
41856
41861
108
de Meis
,
L.
(
2002
)
Ca2+-ATPases (SERCA): energy transduction and heat production in transport ATPases
.
J. Membr. Biol.
188
,
1
9
109
de Meis
,
L.
,
Oliveira
,
G.M.
,
Arruda
,
A.P.
,
Santos
,
R.
,
Costa
,
R.M.
and
Benchimol
,
M.
(
2005
)
The thermogenic activity of rat brown adipose tissue and rabbit white muscle Ca2+-ATPase
.
IUBMB Life
57
,
337
345
110
Morrissette
,
J.M.
,
Franck
,
J.P.
and
Block
,
B.A.
(
2003
)
Characterization of ryanodine receptor and Ca2+-ATPase isoforms in the thermogenic heater organ of blue marlin (Makaira nigricans)
.
J. Exp. Biol.
206
,
805
812
111
Londraville
,
R.L.
,
Cramer
,
T.D.
,
Franck
,
J.P.
,
Tullis
,
A.
and
Block
,
B.A.
(
2000
)
Cloning of a neonatal calcium atpase isoform (SERCA 1B) from extraocular muscle of adult blue marlin (Makaira nigricans)
.
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
127
,
223
233
112
Periasamy
,
M.
,
Maurya
,
S.K.
,
Sahoo
,
S.K.
,
Singh
,
S.
,
Sahoo
,
S.K.
,
Reis
,
F.C.G.
et al (
2017
)
Role of SERCA pump in muscle thermogenesis and metabolism
.
Compr. Physiol.
7
,
879
890
113
Periasamy
,
M.
,
Herrera
,
J.L.
and
Reis
,
F.C.G.
(
2017
)
Skeletal muscle thermogenesis and its role in whole body energy metabolism
.
Diabetes Metab. J.
41
,
327
336
114
Ikeda
,
K.
,
Kang
,
Q.
,
Yoneshiro
,
T.
,
Camporez
,
J.P.
,
Maki
,
H.
,
Homma
,
M.
et al (
2017
)
UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis
.
Nat. Med.
23
,
1454
1465
115
Kazak
,
L.
,
Chouchani
,
E.T.
,
Jedrychowski
,
M.P.
,
Erickson
,
B.K.
,
Shinoda
,
K.
,
Cohen
,
P.
et al (
2015
)
A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat
.
Cell
163
,
643
655
116
Kazak
,
L.
,
Rahbani
,
J.F.
,
Samborska
,
B.
,
Lu
,
G.Z.
,
Jedrychowski
,
M.P.
,
Lajoie
,
M.
et al (
2019
)
Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity
.
Nat. Metab.
1
,
360
370
117
Roesler
,
A.
and
Kazak
,
L.
(
2020
)
UCP1-independent thermogenesis
.
Biochem. J.
477
,
709
725
118
Kazak
,
L.
,
Chouchani
,
E.T.
,
Lu
,
G.Z.
,
Jedrychowski
,
M.P.
,
Bare
,
C.J.
,
Mina
,
A.I.
et al (
2017
)
Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity
.
Cell Metab.
26
,
660
671.e
119
Sponton
,
C.H.
and
Kajimura
,
S.
(
2018
)
Multifaceted roles of beige fat in energy homeostasis beyond UCP1
.
Endocrinology
159
,
2545
2553
120
Kajimura
,
S.
(
2017
)
Adipose tissue in 2016: advances in the understanding of adipose tissue biology
.
Nat. Rev. Endocrinol.
13
,
69
70
121
Mottillo
,
E.P.
,
Ramseyer
,
V.D.
and
Granneman
,
J.G.
(
2018
)
SERCA2b cycles its way to UCP1-independent thermogenesis in beige fat
.
Cell Metab.
27
,
7
9
122
Porter
,
C.
(
2017
)
Quantification of UCP1 function in human brown adipose tissue
.
Adipocyte
6
,
167
174
123
Kalinovich
,
A.V.
,
de Jong
,
J.M.
,
Cannon
,
B.
and
Nedergaard
,
J.
(
2017
)
UCP1 in adipose tissues: two steps to full browning
.
Biochimie
134
,
127
137
124
Ricquier
,
D.
(
2017
)
UCP1, the mitochondrial uncoupling protein of brown adipocyte: a personal contribution and a historical perspective
.
Biochimie
134
,
3
8
125
Kozak
,
L.P.
and
Anunciado-Koza
,
R.
(
2008
)
UCP1: its involvement and utility in obesity
.
Int. J. Obes. (Lond)
32
,
S32
S38
126
Parker
,
N.
,
Crichton
,
P.G.
,
Vidal-Puig
,
A.J.
and
Brand
,
M.D.
(
2009
)
Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria
.
J. Bioenerg. Biomembr.
41
,
335
342
127
Luevano-Martinez
,
L.A.
(
2012
)
Uncoupling proteins (UCP) in unicellular eukaryotes: true UCPs or UCP1-like acting proteins?
FEBS Lett.
586
,
1073
1078
128
Kozak
,
L.P.
and
Koza
,
R.A.
(
1999
)
Mitochondria uncoupling proteins and obesity: molecular and genetic aspects of UCP1
.
Int. J. Obes. Relat. Metab. Disord.
23
,
S33
S37
129
Wu
,
J.
,
Bostrom
,
P.
,
Sparks
,
L.M.
,
Ye
,
L.
,
Choi
,
J.H.
,
Giang
,
A.H.
et al (
2012
)
Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human
.
Cell
150
,
366
376
130
Wu
,
J.
,
Cohen
,
P.
and
Spiegelman
,
B.M.
(
2013
)
Adaptive thermogenesis in adipocytes: is beige the new brown?
Genes Dev.
27
,
234
250
131
Harms
,
M.
and
Seale
,
P.
(
2013
)
Brown and beige fat: development, function and therapeutic potential
.
Nat. Med.
19
,
1252
1263
132
Kajimura
,
S.
,
Spiegelman
,
B.M.
and
Seale
,
P.
(
2015
)
Brown and beige fat: hysiological roles beyond heat generation
.
Cell Metab.
22
,
546
559
133
Chen
,
Y.
,
Ikeda
,
K.
,
Yoneshiro
,
T.
,
Scaramozza
,
A.
,
Tajima
,
K.
,
Wang
,
Q.
et al (
2019
)
Thermal stress induces glycolytic beige fat formation via a myogenic state
.
Nature
565
,
180
185
134
Pollard
,
A.E.
,
Martins
,
L.
,
Muckett
,
P.J.
,
Khadayate
,
S.
,
Bornot
,
A.
,
Clausen
,
M.
et al (
2019
)
AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue
.
Nat. Metab.
1
,
340
349
135
Nishikawa
,
S.
,
Hydo
,
T.
,
Aoyama
,
H.
,
Miyata
,
R.
,
Kumazawa
,
S.
and
Tsuda
,
T.
(
2020
)
Artepillin C, a Key component of Brazilian propolis, induces thermogenesis in inguinal white adipose tissue of mice through a creatine-metabolism-related thermogenic pathway
.
J. Agric. Food. Chem.
68
,
1007
1014
136
Rowland
,
L.A.
,
Bal
,
N.C.
and
Periasamy
,
M.
(
2015
)
The role of skeletal-muscle-based thermogenic mechanisms in vertebrate endothermy
.
Biol. Rev. Camb. Philos. Soc.
90
,
1279
1297
137
Bal
,
N.C.
and
Periasamy
,
M.
(
2020
)
Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis
.
Philos. Trans. R. Soc. Lond. B Biol. Sci.
375
,
20190135
138
Block
,
B.A.
and
Franzini-Armstrong
,
C.
(
1988
)
The structure of the membrane systems in a novel muscle cell modified for heat production
.
J. Cell Biol.
107
,
1099
1112
139
Block
,
B.A.
,
O'Brien
,
J.
and
Meissner
,
G.
(
1994
)
Characterization of the sarcoplasmic reticulum proteins in the thermogenic muscles of fish
.
J. Cell Biol.
127
,
1275
1287
140
Block
,
B.A.
(
1994
)
Thermogenesis in muscle
.
Annu. Rev. Physiol.
56
,
535
577
141
Bal
,
N.C.
,
Maurya
,
S.K.
,
Sopariwala
,
D.H.
,
Sahoo
,
S.K.
,
Gupta
,
S.C.
,
Shaikh
,
S.A.
et al (
2012
)
Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals
.
Nat. Med.
18
,
1575
1579
142
Arruda
,
A.P.
,
Ketzer
,
L.A.
,
Nigro
,
M.
,
Galina
,
A.
,
Carvalho
,
D.P.
and
de Meis
,
L.
(
2008
)
Cold tolerance in hypothyroid rabbits: role of skeletal muscle mitochondria and sarcoplasmic reticulum Ca2+ ATPase isoform 1 heat production
.
Endocrinology
149
,
6262
6271
143
de Meis
,
L.
,
Arruda
,
A.P.
,
da Costa
,
R.M.
and
Benchimol
,
M.
(
2006
)
Identification of a Ca2+-ATPase in brown adipose tissue mitochondria: regulation of thermogenesis by ATP and Ca2+
.
J. Biol. Chem.
281
,
16384
16390
144
Nedergaard
,
J.
,
Golozoubova
,
V.
,
Matthias
,
A.
,
Shabalina
,
I.
,
Ohba
,
K.
,
Ohlson
,
K.
et al (
2001
)
Life without UCP1: mitochondrial, cellular and organismal characteristics of the UCP1-ablated mice
.
Biochem. Soc. Trans.
29
,
756
763
145
Enerback
,
S.
,
Jacobsson
,
A.
,
Simpson
,
E.M.
,
Guerra
,
C.
,
Yamashita
,
H.
,
Harper
,
M.E.
et al (
1997
)
Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese
.
Nature
387
,
90
94
146
Bal
,
N.C.
,
Maurya
,
S.K.
,
Pani
,
S.
,
Sethy
,
C.
,
Banerjee
,
A.
,
Das
,
S.
et al (
2017
)
Mild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners?
Biosci. Rep.
37
,
BSR20171087
147
Rowland
,
L.A.
,
Bal
,
N.C.
,
Kozak
,
L.P.
and
Periasamy
,
M.
(
2015
)
Uncoupling protein 1 and sarcolipin are required to maintain optimal thermogenesis, and loss of both systems compromises survival of mice under cold stress
.
J. Biol. Chem.
290
,
12282
12289
148
Rosenberg
,
H.
,
Pollock
,
N.
,
Schiemann
,
A.
,
Bulger
,
T.
and
Stowell
,
K.
(
2015
)
Malignant hyperthermia: a review
.
Orphanet. J. Rare Dis.
10
,
93
149
Schneiderbanger
,
D.
,
Johannsen
,
S.
,
Roewer
,
N.
and
Schuster
,
F.
(
2014
)
Management of malignant hyperthermia: diagnosis and treatment
.
Ther. Clin. Risk Manag.
10
,
355
362
150
Bicudo
,
J.E.
,
Bianco
,
A.C.
and
Vianna
,
C.R.
(
2002
)
Adaptive thermogenesis in hummingbirds
.
J. Exp. Biol.
205
,
2267
2273
PMID:
[PubMed]
151
Schweizer
,
S.
,
Oeckl
,
J.
,
Klingenspor
,
M.
and
Fromme
,
T.
(
2018
)
Substrate fluxes in brown adipocytes upon adrenergic stimulation and uncoupling protein 1 ablation
.
Life Sci. Alliance
1
,
e201800136
152
Granneman
,
J.G.
,
Burnazi
,
M.
,
Zhu
,
Z.
and
Schwamb
,
L.A.
(
2003
)
White adipose tissue contributes to UCP1-independent thermogenesis
.
Am. J. Physiol. Endocrinol. Metab.
285
,
E1230
E1236
153
Mottillo
,
E.P.
,
Balasubramanian
,
P.
,
Lee
,
Y.H.
,
Weng
,
C.
,
Kershaw
,
E.E.
and
Granneman
,
J.G.
(
2014
)
Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation
.
J. Lipid Res.
55
,
2276
2286
154
Flachs
,
P.
,
Adamcova
,
K.
,
Zouhar
,
P.
,
Marques
,
C.
,
Janovska
,
P.
,
Viegas
,
I.
et al (
2017
)
Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype
.
Int. J. Obes. (Lond)
41
,
997
155
Flachs
,
P.
,
Rossmeisl
,
M.
,
Kuda
,
O.
and
Kopecky
,
J.
(
2013
)
Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype
.
Biochim. Biophys. Acta
1831
,
986
1003
156
Kramarova
,
T.V.
,
Shabalina
,
I.G.
,
Andersson
,
U.
,
Westerberg
,
R.
,
Carlberg
,
I.
,
Houstek
,
J.
et al (
2008
)
Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform
.
FASEB J.
22
,
55
63
157
Bal
,
N.C.
,
Singh
,
S.
,
Reis
,
F.C.G.
,
Maurya
,
S.K.
,
Pani
,
S.
,
Rowland
,
L.A.
et al (
2017
)
Both brown adipose tissue and skeletal muscle thermogenesis processes are activated during mild to severe cold adaptation in mice
.
J. Biol. Chem.
292
,
16616
16625
158
Sanchez-Gurmaches
,
J.
,
Hung
,
C.M.
and
Guertin
,
D.A.
(
2016
)
Emerging complexities in adipocyte origins and identity
.
Trends Cell Biol.
26
,
313
326
159
Timmons
,
J.A.
,
Wennmalm
,
K.
,
Larsson
,
O.
,
Walden
,
T.B.
,
Lassmann
,
T.
,
Petrovic
,
N.
et al (
2007
)
Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages
.
Proc. Natl. Acad. Sci. U.S.A.
104
,
4401
4406
160
Seale
,
P.
,
Bjork
,
B.
,
Yang
,
W.
,
Kajimura
,
S.
,
Chin
,
S.
,
Kuang
,
S.
et al (
2008
)
PRDM16 controls a brown fat/skeletal muscle switch
.
Nature
454
,
961
967
161
Sharma
,
A.
,
Huard
,
C.
,
Vernochet
,
C.
,
Ziemek
,
D.
,
Knowlton
,
K.M.
,
Tyminski
,
E.
et al (
2014
)
Brown fat determination and development from muscle precursor cells by novel action of bone morphogenetic protein 6
.
PLoS One
9
,
e92608
162
Berry
,
R.
and
Rodeheffer
,
M.S.
(
2013
)
Characterization of the adipocyte cellular lineage in vivo
.
Nat. Cell Biol.
15
,
302
308
163
Lee
,
Y.H.
,
Petkova
,
A.P.
,
Mottillo
,
E.P.
and
Granneman
,
J.G.
(
2012
)
In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding
.
Cell Metab.
15
,
480
491
164
Sharp
,
L.Z.
,
Shinoda
,
K.
,
Ohno
,
H.
,
Scheel
,
D.W.
,
Tomoda
,
E.
,
Ruiz
,
L.
et al (
2012
)
Human BAT possesses molecular signatures that resemble beige/brite cells
.
PLoS One
7
,
e49452
165
Lidell
,
M.E.
,
Betz
,
M.J.
,
Dahlqvist Leinhard
,
O.
,
Heglind
,
M.
,
Elander
,
L.
,
Slawik
,
M.
et al (
2013
)
Evidence for two types of brown adipose tissue in humans
.
Nat. Med.
19
,
631
634
166
Fischer
,
A.W.
,
Cannon
,
B.
and
Nedergaard
,
J.
(
2018
)
Optimal housing temperatures for mice to mimic the thermal environment of humans: an experimental study
.
Mol. Metab.
7
,
161
170
167
Skop
,
V.
,
Guo
,
J.
,
Liu
,
N.
,
Xiao
,
C.
,
Hall
,
K.D.
,
Gavrilova
,
O.
et al (
2020
)
Mouse thermoregulation: introducing the concept of the thermoneutral point
.
Cell Rep.
31
,
107501
168
Merrick
,
D.
,
Sakers
,
A.
,
Irgebay
,
Z.
,
Okada
,
C.
,
Calvert
,
C.
,
Morley
,
M.P.
et al (
2019
)
Identification of a mesenchymal progenitor cell hierarchy in adipose tissue
.
Science
364
,
eaav2501
169
Spaethling
,
J.M.
,
Sanchez-Alavez
,
M.
,
Lee
,
J.
,
Xia
,
F.C.
,
Dueck
,
H.
,
Wang
,
W.
et al (
2016
)
Single-cell transcriptomics and functional target validation of brown adipocytes show their complex roles in metabolic homeostasis
.
FASEB J.
30
,
81
92
170
Raajendiran
,
A.
,
Ooi
,
G.
,
Bayliss
,
J.
,
O'Brien
,
P.E.
,
Schittenhelm
,
R.B.
,
Clark
,
A.K.
et al (
2019
)
Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues
.
Cell Rep.
27
,
1528
1540.e1527
171
Ohno
,
H.
,
Shinoda
,
K.
,
Spiegelman
,
B.M.
and
Kajimura
,
S.
(
2012
)
PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein
.
Cell Metab.
15
,
395
404
172
Seale
,
P.
,
Conroe
,
H.M.
,
Estall
,
J.
,
Kajimura
,
S.
,
Frontini
,
A.
,
Ishibashi
,
J.
et al (
2011
)
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
.
J. Clin. Invest.
121
,
96
105
173
Harms
,
M.J.
,
Ishibashi
,
J.
,
Wang
,
W.
,
Lim
,
H.W.
,
Goyama
,
S.
,
Sato
,
T.
et al (
2014
)
Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice
.
Cell Metab.
19
,
593
604
174
Kajimura
,
S.
(
2015
)
Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway
.
Int. J. Obes. Suppl.
5
,
S11
S14
175
Kajimura
,
S.
,
Seale
,
P.
,
Tomaru
,
T.
,
Erdjument-Bromage
,
H.
,
Cooper
,
M.P.
,
Ruas
,
J.L.
et al (
2008
)
Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex
.
Genes Dev.
22
,
1397
1409
176
Ohno
,
H.
,
Shinoda
,
K.
,
Ohyama
,
K.
,
Sharp
,
L.Z.
and
Kajimura
,
S.
(
2013
)
EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex
.
Nature
504
,
163
167
177
Kajimura
,
S.
,
Seale
,
P.
,
Kubota
,
K.
,
Lunsford
,
E.
,
Frangioni
,
J.V.
,
Gygi
,
S.P.
et al (
2009
)
Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex
.
Nature
460
,
1154
1158
178
Cohen
,
P.
,
Levy
,
J.D.
,
Zhang
,
Y.
,
Frontini
,
A.
,
Kolodin
,
D.P.
,
Svensson
,
K.J.
et al (
2014
)
Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch
.
Cell
156
,
304
316
179
Ishibashi
,
J.
and
Seale
,
P.
(
2015
)
Functions of Prdm16 in thermogenic fat cells
.
Temperature (Austin)
2
,
65
72
180
Hauner
,
H.
(
2002
)
The mode of action of thiazolidinediones
.
Diabetes Metab. Res. Rev.
18
,
S10
S15
181
Vishvanath
,
L.
,
MacPherson
,
K.A.
,
Hepler
,
C.
,
Wang
,
Q.A.
,
Shao
,
M.
,
Spurgin
,
S.B.
et al (
2016
)
Pdgfrbeta+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice
.
Cell Metab.
23
,
350
359
182
Gupta
,
R.K.
,
Arany
,
Z.
,
Seale
,
P.
,
Mepani
,
R.J.
,
Ye
,
L.
,
Conroe
,
H.M.
et al (
2010
)
Transcriptional control of preadipocyte determination by Zfp423
.
Nature
464
,
619
623
183
Berry
,
R.
,
Rodeheffer
,
M.S.
,
Rosen
,
C.J.
and
Horowitz
,
M.C.
(
2015
)
Adipose tissue residing progenitors (adipocyte lineage progenitors and adipose derived stem cells (ADSC)
.
Curr. Mol. Biol. Rep.
1
,
101
109
184
Kruglikov
,
I.L.
and
Scherer
,
P.E.
(
2017
)
Adipocyte-myofibroblast transition as a possible pathophysiological step in androgenetic alopecia
.
Exp. Dermatol.
26
,
522
523
185
Kruglikov
,
I.L.
,
Scherer
,
P.E.
and
Wollina
,
U.
(
2016
)
Are dermal adipocytes involved in psoriasis?
Exp. Dermatol.
25
,
812
813
186
Kruglikov
,
I.L.
,
Zhang
,
Z.
and
Scherer
,
P.E.
(
2019
)
The role of immature and mature adipocytes in hair cycling
.
Trends Endocrinol. Metab.
30
,
93
105
187
Marangoni
,
R.G.
,
Korman
,
B.D.
,
Wei
,
J.
,
Wood
,
T.A.
,
Graham
,
L.V.
,
Whitfield
,
M.L.
et al (
2015
)
Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors
.
Arthritis Rheumatol.
67
,
1062
1073
188
Nicu
,
C.
,
Pople
,
J.
,
Bonsell
,
L.
,
Bhogal
,
R.
,
Ansell
,
D.M.
and
Paus
,
R.
(
2018
)
A guide to studying human dermal adipocytes in situ
.
Exp. Dermatol.
27
,
589
602
189
Wang
,
W.
and
Seale
,
P.
(
2016
)
Control of brown and beige fat development
.
Nat. Rev. Mol. Cell Biol.
17
,
691
702
190
Shapira
,
S.N.
and
Seale
,
P.
(
2019
)
Transcriptional control of brown and beige fat development and function
.
Obesity (Silver Spring)
27
,
13
21
191
Nagano
,
G.
,
Ohno
,
H.
,
Oki
,
K.
,
Kobuke
,
K.
,
Shiwa
,
T.
,
Yoneda
,
M.
et al (
2015
)
Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression
.
PLoS One
10
,
e0122584
192
Dempersmier
,
J.
,
Sambeat
,
A.
,
Gulyaeva
,
O.
,
Paul
,
S.M.
,
Hudak
,
C.S.
,
Raposo
,
H.F.
et al (
2015
)
Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat
.
Mol. Cell
57
,
235
246
193
Okla
,
M.
,
Ha
,
J.H.
,
Temel
,
R.E.
and
Chung
,
S.
(
2015
)
BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes
.
Lipids
50
,
111
120
194
Wang
,
W.
,
Kissig
,
M.
,
Rajakumari
,
S.
,
Huang
,
L.
,
Lim
,
H.W.
,
Won
,
K.J.
et al (
2014
)
Ebf2 is a selective marker of brown and beige adipogenic precursor cells
.
Proc. Natl. Acad. Sci. U.S.A.
111
,
14466
14471
195
Stine
,
R.R.
,
Shapira
,
S.N.
,
Lim
,
H.W.
,
Ishibashi
,
J.
,
Harms
,
M.
,
Won
,
K.J.
et al (
2016
)
EBF2 promotes the recruitment of beige adipocytes in white adipose tissue
.
Mol. Metab.
5
,
57
65
196
Morroni
,
M.
,
Giordano
,
A.
,
Zingaretti
,
M.C.
,
Boiani
,
R.
,
De Matteis
,
R.
,
Kahn
,
B.B.
et al (
2004
)
Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland
.
Proc. Natl. Acad. Sci. U.S.A.
101
,
16801
16806
197
Giordano
,
A.
,
Smorlesi
,
A.
,
Frontini
,
A.
,
Barbatelli
,
G.
and
Cinti
,
S.
(
2014
)
White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ
.
Eur. J. Endocrinol.
170
,
R159
R171
https://doi.org/10.1530/EJE-13-0945
198
Cinti
,
S.
(
2018
)
Pink adipocytes
.
Trends Endocrinol. Metab.
29
,
651
666
199
Wang
,
Q.A.
,
Song
,
A.
,
Chen
,
W.
,
Schwalie
,
P.C.
,
Zhang
,
F.
,
Vishvanath
,
L.
et al (
2018
)
Reversible de-differentiation of mature white adipocytes into preadipocyte-like precursors during lactation
.
Cell Metab.
28
,
282
288
200
Festuccia
,
W.T.
,
Blanchard
,
P.G.
and
Deshaies
,
Y.
(
2011
)
Control of brown adipose tissue glucose and lipid metabolism by PPARγ
.
Front. Endocrinol. (Lausanne)
2
,
84
201
Rajakumari
,
S.
,
Wu
,
J.
,
Ishibashi
,
J.
,
Lim
,
H.W.
,
Giang
,
A.H.
,
Won
,
K.J.
et al (
2013
)
EBF2 determines and maintains brown adipocyte identity
.
Cell Metab.
17
,
562
574
202
Shapira
,
S.N.
,
Lim
,
H.W.
,
Rajakumari
,
S.
,
Sakers
,
A.P.
,
Ishibashi
,
J.
,
Harms
,
M.J.
et al (
2017
)
EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex
.
Genes Dev.
31
,
660
673
203
Kajimura
,
S.
(
2015
)
Engineering fat cell fate to fight obesity and metabolic diseases
.
Keio J. Med.
64
,
65
204
Wang
,
J.
and
Tontonoz
,
P.
(
2017
)
Pioneering EBF2 remodels the brown fat chromatin landscape
.
Genes Dev.
31
,
632
633
205
Yamamoto
,
K.
,
Sakaguchi
,
M.
,
Medina
,
R.J.
,
Niida
,
A.
,
Sakaguchi
,
Y.
,
Miyazaki
,
M.
et al (
2010
)
Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15
.
Biochem. Biophys. Res. Commun.
400
,
175
180
206
Kissig
,
M.
,
Shapira
,
S.N.
and
Seale
,
P.
(
2016
)
Snapshot: brown and beige adipose thermogenesis
.
Cell
166
,
258
258.e251
207
Giordano
,
A.
,
Perugini
,
J.
,
Kristensen
,
D.M.
,
Sartini
,
L.
,
Frontini
,
A.
,
Kajimura
,
S.
et al (
2017
)
Mammary alveolar epithelial cells convert to brown adipocytes in post-lactating mice
.
J. Cell Physiol.
232
,
2923
2928
208
Li
,
X.
,
Liu
,
J.
,
Wang
,
G.
,
Yu
,
J.
,
Sheng
,
Y.
,
Wang
,
C.
et al (
2015
)
Determination of UCP1 expression in subcutaneous and perirenal adipose tissues of patients with hypertension
.
Endocrine
50
,
413
423
209
de Jong
,
J.M.
,
Larsson
,
O.
,
Cannon
,
B.
and
Nedergaard
,
J.
(
2015
)
A stringent validation of mouse adipose tissue identity markers
.
Am. J. Physiol. Endocrinol. Metab.
308
,
E1085
E1105
210
Chau
,
Y.Y.
,
Bandiera
,
R.
,
Serrels
,
A.
,
Martinez-Estrada
,
O.M.
,
Qing
,
W.
,
Lee
,
M.
et al (
2014
)
Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source
.
Nat. Cell Biol.
16
,
367
375
211
Shan
,
T.
,
Liang
,
X.
,
Bi
,
P.
,
Zhang
,
P.
,
Liu
,
W.
and
Kuang
,
S.
(
2013
)
Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues
.
J. Lipid Res.
54
,
2214
2224
212
Silva
,
K.R.
and
Baptista
,
L.S.
(
2019
)
Adipose-derived stromal/stem cells from different adipose depots in obesity development
.
World J. Stem Cells
11
,
147
166
213
Tran
,
K.V.
,
Gealekman
,
O.
,
Frontini
,
A.
,
Zingaretti
,
M.C.
,
Morroni
,
M.
,
Giordano
,
A.
et al (
2012
)
The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells
.
Cell Metab.
15
,
222
229
214
Rosso
,
R.
and
Lucioni
,
M.
(
2006
)
Normal and neoplastic cells of brown adipose tissue express the adhesion molecule CD31
.
Arch. Pathol. Lab. Med.
130
,
480
482
215
van Marken Lichtenbelt
,
W.D.
,
Vanhommerig
,
J.W.
,
Smulders
,
N.M.
,
Drossaerts
,
J.M.
,
Kemerink
,
G.J.
,
Bouvy
,
N.D.
et al (
2009
)
Cold-activated brown adipose tissue in healthy men
.
N. Engl. J. Med.
360
,
1500
1508
216
Saito
,
M.
,
Okamatsu-Ogura
,
Y.
,
Matsushita
,
M.
,
Watanabe
,
K.
,
Yoneshiro
,
T.
,
Nio-Kobayashi
,
J.
et al (
2009
)
High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity
.
Diabetes
58
,
1526
1531
217
Cypess
,
A.M.
,
Lehman
,
S.
,
Williams
,
G.
,
Tal
,
I.
,
Rodman
,
D.
,
Goldfine
,
A.B.
et al (
2009
)
Identification and importance of brown adipose tissue in adult humans
.
N. Engl. J. Med.
360
,
1509
1517
218
Andersson
,
J.
,
Lundstrom
,
E.
,
Engstrom
,
M.
,
Lubberink
,
M.
,
Ahlstrom
,
H.
and
Kullberg
,
J.
(
2019
)
Estimating the cold-induced brown adipose tissue glucose uptake rate measured by (18)F-FDG PET using infrared thermography and water-fat separated MRI
.
Sci. Rep.
9
,
12358
219
Patsouris
,
D.
,
Qi
,
P.
,
Abdullahi
,
A.
,
Stanojcic
,
M.
,
Chen
,
P.
,
Parousis
,
A.
et al (
2015
)
Burn induces browning of the subcutaneous white adipose tissue in mice and humans
.
Cell Rep.
13
,
1538
1544
220
Tsoli
,
M.
,
Moore
,
M.
,
Burg
,
D.
,
Painter
,
A.
,
Taylor
,
R.
,
Lockie
,
S.H.
et al (
2012
)
Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice
.
Cancer Res.
72
,
4372
4382
221
Vaitkus
,
J.A.
and
Celi
,
F.S.
(
2017
)
The role of adipose tissue in cancer-associated cachexia
.
Exp. Biol. Med. (Maywood)
242
,
473
481
222
Wang
,
B.
,
Zhang
,
F.
,
Zhang
,
H.
,
Wang
,
Z.
,
Ma
,
Y.N.
,
Zhu
,
M.J.
et al (
2017
)
Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia
.
Oncotarget
8
,
100411
100420
223
Hu
,
W.
,
Ru
,
Z.
,
Xiao
,
W.
,
Xiong
,
Z.
,
Wang
,
C.
,
Yuan
,
C.
et al (
2018
)
Adipose tissue browning in cancer-associated cachexia can be attenuated by inhibition of exosome generation
.
Biochem. Biophys. Res. Commun.
506
,
122
129
224
Daas
,
S.I.
,
Rizeq
,
B.R.
and
Nasrallah
,
G.K.
(
2018
)
Adipose tissue dysfunction in cancer cachexia
.
J. Cell Physiol.
234
,
13
22
225
Abdullahi
,
A.
,
Samadi
,
O.
,
Auger
,
C.
,
Kanagalingam
,
T.
,
Boehning
,
D.
,
Bi
,
S.
et al (
2019
)
Browning of white adipose tissue after a burn injury promotes hepatic steatosis and dysfunction
.
Cell Death Dis.
10
,
870
226
Broeders
,
E.P.
,
Vijgen
,
G.H.
,
Havekes
,
B.
,
Bouvy
,
N.D.
,
Mottaghy
,
F.M.
,
Kars
,
M.
et al (
2016
)
Thyroid hormone activates brown adipose tissue and increases non-shivering thermogenesis–a cohort study in a group of thyroid carcinoma patients
.
PLoS One
11
,
e0145049
227
Broeders
,
E.P.M.
,
Vijgen
,
G.
,
Havekes
,
B.
,
Bouvy
,
N.D.
,
Mottaghy
,
F.M.
,
Kars
,
M.
et al (
2018
)
Correction: thyroid hormone activates brown adipose tissue and increases non-shivering thermogenesis-A cohort study in a group of thyroid carcinoma patients
.
PLoS One
13
,
e0209225
228
Bostrom
,
P.
,
Wu
,
J.
,
Jedrychowski
,
M.P.
,
Korde
,
A.
,
Ye
,
L.
,
Lo
,
J.C.
et al (
2012
)
A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
.
Nature
481
,
463
468
229
Crujeiras
,
A.B.
,
Pardo
,
M.
and
Casanueva
,
F.F.
(
2015
)
Irisin: ‘fat’ or artefact
.
Clin. Endocrinol. (Oxf)
82
,
467
474
230
Elsen
,
M.
,
Raschke
,
S.
and
Eckel
,
J.
(
2014
)
Browning of white fat: does irisin play a role in humans?
J. Endocrinol.
222
,
R25
R38
231
Pukajlo
,
K.
,
Laczmanski
,
L.
,
Kolackov
,
K.
,
Kuliczkowska-Plaksej
,
J.
,
Bolanowski
,
M.
,
Milewicz
,
A.
et al (
2015
)
Irisin plasma concentration in PCOS and healthy subjects is related to body fat content and android fat distribution
.
Gynecol. Endocrinol.
31
,
907
911
232
Kaneda
,
H.
,
Nakajima
,
T.
,
Haruyama
,
A.
,
Shibasaki
,
I.
,
Hasegawa
,
T.
,
Sawaguchi
,
T.
et al (
2018
)
Association of serum concentrations of irisin and the adipokines adiponectin and leptin with epicardial fat in cardiovascular surgery patients
.
PLoS One
13
,
e0201499
233
Lee
,
P.
,
Linderman
,
J.D.
,
Smith
,
S.
,
Brychta
,
R.J.
,
Wang
,
J.
,
Idelson
,
C.
et al (
2014
)
Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
.
Cell Metab.
19
,
302
309
234
Nedergaard
,
J.
and
Cannon
,
B.
(
2013
)
UCP1 mRNA does not produce heat
.
Biochim. Biophys Acta
1831
,
943
949
235
Szabo
,
I.
and
Zoratti
,
M.
(
2017
)
Now UCP(rotein), Now you don't: UCP1 is not mandatory for thermogenesis
.
Cell Metab.
25
,
761
762
236
Keipert
,
S.
and
Jastroch
,
M.
(
2014
)
Brite/beige fat and UCP1 - is it thermogenesis?
Biochim. Biophys. Acta
1837
,
1075
1082
237
Li
,
Y.
,
Fromme
,
T.
and
Klingenspor
,
M.
(
2017
)
Meaningful respirometric measurements of UCP1-mediated thermogenesis
.
Biochimie
134
,
56
61
238
Meyer
,
C.W.
,
Willershauser
,
M.
,
Jastroch
,
M.
,
Rourke
,
B.C.
,
Fromme
,
T.
,
Oelkrug
,
R.
et al (
2010
)
Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
299
,
R1396
R1406
239
Grimpo
,
K.
,
Volker
,
M.N.
,
Heppe
,
E.N.
,
Braun
,
S.
,
Heverhagen
,
J.T.
and
Heldmaier
,
G.
(
2014
)
Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance
.
J. Lipid Res.
55
,
398
409
240
Yamashita
,
H.
,
Ohira
,
Y.
,
Wakatsuki
,
T.
,
Yamamoto
,
M.
,
Kizaki
,
T.
,
Oh-ishi
,
S.
et al (
1995
)
Increased growth of brown adipose tissue but its reduced thermogenic activity in creatine-depleted rats fed beta-guanidinopropionic acid
.
Biochim. Biophys. Acta
1230
,
69
73
241
Bertholet
,
A.M.
,
Kazak
,
L.
,
Chouchani
,
E.T.
,
Bogaczynska
,
M.G.
,
Paranjpe
,
I.
,
Wainwright
,
G.L.
et al (
2017
)
Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling
.
Cell Metab.
25
,
811
822.e814
242
Berlet
,
H.H.
,
Bonsmann
,
I.
and
Birringer
,
H.
(
1976
)
Occurrence of free creatine, phosphocreatine and creatine phosphokinase in adipose tissue
.
Biochim. Biophys. Acta
437
,
166
174
243
Arch
,
J.R.
(
2011
)
Challenges in beta(3)-adrenoceptor agonist drug development
.
Ther. Adv. Endocrinol. Metab.
2
,
59
64
244
Ye
,
L.
,
Wu
,
J.
,
Cohen
,
P.
,
Kazak
,
L.
,
Khandekar
,
M.J.
,
Jedrychowski
,
M.P.
et al (
2013
)
Fat cells directly sense temperature to activate thermogenesis
.
Proc. Natl. Acad. Sci. U.S.A.
110
,
12480
12485
245
Razzoli
,
M.
,
Frontini
,
A.
,
Gurney
,
A.
,
Mondini
,
E.
,
Cubuk
,
C.
,
Katz
,
L.S.
et al (
2016
)
Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis
.
Mol. Metab.
5
,
19
33
246
Bachman
,
E.S.
,
Dhillon
,
H.
,
Zhang
,
C.Y.
,
Cinti
,
S.
,
Bianco
,
A.C.
,
Kobilka
,
B.K.
et al (
2002
)
betaAR signaling required for diet-induced thermogenesis and obesity resistance
.
Science
297
,
843
845
247
Wu
,
L.
,
Zhang
,
L.
,
Li
,
B.
,
Jiang
,
H.
,
Duan
,
Y.
,
Xie
,
Z.
et al (
2018
)
AMP-Activated Protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue
.
Front. Physiol.
9
,
122
248
Alcala
,
M.
,
Calderon-Dominguez
,
M.
,
Bustos
,
E.
,
Ramos
,
P.
,
Casals
,
N.
,
Serra
,
D.
et al (
2017
)
Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice
.
Sci. Rep.
7
,
16082
249
Weisberg
,
S.P.
,
McCann
,
D.
,
Desai
,
M.
,
Rosenbaum
,
M.
,
Leibel
,
R.L.
and
Ferrante
, Jr,
A.W.
(
2003
)
Obesity is associated with macrophage accumulation in adipose tissue
.
J. Clin. Invest.
112
,
1796
1808
250
Ye
,
R.
,
Wang
,
Q.A.
,
Tao
,
C.
,
Vishvanath
,
L.
,
Shao
,
M.
,
McDonald
,
J.G.
et al (
2015
)
Impact of tamoxifen on adipocyte lineage tracing: inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase
.
Mol. Metab.
4
,
771
778
251
Rondini
,
E.A.
and
Granneman
,
J.G.
(
2020
)
Single cell approaches to address adipose tissue stromal cell heterogeneity
.
Biochem. J.
477
,
583
600
252
Himms-Hagen
,
J.
,
Melnyk
,
A.
,
Zingaretti
,
M.C.
,
Ceresi
,
E.
,
Barbatelli
,
G.
and
Cinti
,
S.
(
2000
)
Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes
.
Am. J. Physiol. Cell Physiol.
279
,
C670
C681
253
Vitali
,
A.
,
Murano
,
I.
,
Zingaretti
,
M.C.
,
Frontini
,
A.
,
Ricquier
,
D.
and
Cinti
,
S.
(
2012
)
The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes
.
J. Lipid Res.
53
,
619
629
254
Wang
,
Q.A.
,
Tao
,
C.
,
Gupta
,
R.K.
and
Scherer
,
P.E.
(
2013
)
Tracking adipogenesis during white adipose tissue development, expansion and regeneration
.
Nat. Med.
19
,
1338
1344
255
Ortega-Molina
,
A.
,
Efeyan
,
A.
,
Lopez-Guadamillas
,
E.
,
Munoz-Martin
,
M.
,
Gomez-Lopez
,
G.
,
Canamero
,
M.
et al (
2012
)
Pten positively regulates brown adipose function, energy expenditure, and longevity
.
Cell Metab.
15
,
382
394
256
Shao
,
M.
,
Vishvanath
,
L.
,
Busbuso
,
N.C.
,
Hepler
,
C.
,
Shan
,
B.
,
Sharma
,
A.X.
et al (
2018
)
De novo adipocyte differentiation from Pdgfrbeta(+) preadipocytes protects against pathologic visceral adipose expansion in obesity
.
Nat. Commun.
9
,
890
257
Shao
,
M.
,
Ishibashi
,
J.
,
Kusminski
,
C.M.
,
Wang
,
Q.A.
,
Hepler
,
C.
,
Vishvanath
,
L.
et al (
2016
)
Zfp423 maintains white adipocyte identity through suppression of the beige cell thermogenic gene program
.
Cell Metab.
23
,
1167
1184
258
Vijay
,
J.
,
Gauthier
,
M.-F.
,
Biswell
,
R.L.
,
Louiselle
,
D.A.
,
Johnston
,
J.J.
,
Cheung
,
W.A.
et al (
2020
)
Single-cell analysis of human adipose tissue identifies depot- and disease-specific cell types
.
Nat. Metab.
2
,
97
109
259
Zhou
,
W.
,
Lin
,
J.
,
Zhao
,
K.
,
Jin
,
K.
,
He
,
Q.
,
Hu
,
Y.
et al (
2019
)
Single-cell profiles and clinically useful properties of human mesenchymal stem cells of adipose and bone marrow origin
.
Am. J. Sports Med.
47
,
1722
1733
260
Gu
,
W.
,
Nowak
,
W.N.
,
Xie
,
Y.
,
Le Bras
,
A.
,
Hu
,
Y.
,
Deng
,
J.
et al (
2019
)
Single-cell RNA-sequencing and metabolomics analyses reveal the contribution of perivascular adipose tissue stem cells to vascular remodeling
.
Arterioscler. Thromb. Vasc. Biol.
39
,
2049
2066
261
Hepler
,
C.
,
Shan
,
B.
,
Zhang
,
Q.
,
Henry
,
G.H.
,
Shao
,
M.
,
Vishvanath
,
L.
et al (
2018
)
Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice
.
eLife
7
,
e39636
262
Pforringer
,
D.
,
Aitzetmuller
,
M.M.
,
Brett
,
E.A.
,
Houschyar
,
K.S.
,
Schafer
,
R.
,
van Griensven
,
M.
et al (
2018
)
Single-cell gene expression analysis and evaluation of the therapeutic function of murine adipose-derived stromal cells (ASCs) from the Subcutaneous and Visceral Compartment
.
Stem Cells Int.
2018
,
2183736
263
Liu
,
X.
,
Xiang
,
Q.
,
Xu
,
F.
,
Huang
,
J.
,
Yu
,
N.
,
Zhang
,
Q.
et al (
2019
)
Single-cell RNA-seq of cultured human adipose-derived mesenchymal stem cells
.
Sci. Data
6
,
190031
264
Schwalie
,
P.C.
,
Dong
,
H.
,
Zachara
,
M.
,
Russeil
,
J.
,
Alpern
,
D.
,
Akchiche
,
N.
et al (
2018
)
A stromal cell population that inhibits adipogenesis in mammalian fat depots
.
Nature
559
,
103
108
265
Burl
,
R.B.
,
Ramseyer
,
V.D.
,
Rondini
,
E.A.
,
Pique-Regi
,
R.
,
Lee
,
Y.H.
and
Granneman
,
J.G.
(
2018
)
Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling
.
Cell Metab.
28
,
300
309.e304
266
Li
,
X.
,
Ma
,
T.
,
Sun
,
J.
,
Shen
,
M.
,
Xue
,
X.
,
Chen
,
Y.
et al (
2019
)
Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases
.
Stem Cell Res. Ther.
10
,
196
267
Mu
,
J.
,
Bakreen
,
A.
,
Juntunen
,
M.
,
Korhonen
,
P.
,
Oinonen
,
E.
,
Cui
,
L.
et al (
2019
)
Combined adipose tissue-derived mesenchymal stem cell therapy and rehabilitation in experimental stroke
.
Front. Neurol.
10
,
235
268
Wu
,
L.
,
Cai
,
X.
,
Zhang
,
S.
,
Karperien
,
M.
and
Lin
,
Y.
(
2013
)
Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine
.
J. Cell Physiol.
228
,
938
944
269
Pak
,
J.
,
Lee
,
J.H.
,
Pak
,
N.
,
Pak
,
Y.
,
Park
,
K.S.
,
Jeon
,
J.H.
et al (
2018
)
Cartilage regeneration in humans with adipose tissue-derived stem cells and adipose stromal vascular fraction cells: updated status
.
Int. J. Mol. Sci.
19
,
2146
270
Gu
,
X.
,
Li
,
C.
,
Yin
,
F.
and
Yang
,
G.
(
2018
)
Adipose-derived stem cells in articular cartilage regeneration: current concepts and optimization strategies
.
Histol. Histopathol.
33
,
639
653
271
Liqing
,
Y.
,
Jia
,
G.
,
Jiqing
,
C.
,
Ran
,
G.
,
Fei
,
C.
,
Jie
,
K.
et al (
2011
)
Directed differentiation of motor neuron cell-like cells from human adipose-derived stem cells in vitro
.
Neuroreport
22
,
370
373
272
Gao
,
S.
,
Zhao
,
P.
,
Lin
,
C.
,
Sun
,
Y.
,
Wang
,
Y.
,
Zhou
,
Z.
et al (
2014
)
Differentiation of human adipose-derived stem cells into neuron-like cells which are compatible with photocurable three-dimensional scaffolds
.
Tissue Eng. Part A
20
,
1271
1284
273
Gao
,
S.
,
Guo
,
X.
,
Zhao
,
S.
,
Jin
,
Y.
,
Zhou
,
F.
,
Yuan
,
P.
et al (
2019
)
Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury
.
Cell Death Dis.
10
,
597
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