Adipose tissue is a central regulator of metabolism and an important pharmacological target to treat the metabolic consequences of obesity, such as insulin resistance and dyslipidemia. Among the various cellular compartments, the adipocyte cell surface is especially appealing as a drug target as it contains various proteins that when activated or inhibited promote adipocyte health, change its endocrine function and eventually maintain or restore whole-body insulin sensitivity. In addition, cell surface proteins are readily accessible by various drug classes. However, targeting individual cell surface proteins in adipocytes has been difficult due to important functions of these proteins outside adipose tissue, raising various safety concerns. Thus, one of the biggest challenges is the lack of adipose selective surface proteins and/or targeting reagents. Here, we discuss several receptor families with an important function in adipogenesis and mature adipocytes to highlight the complexity at the cell surface and illustrate the problems with identifying adipose selective proteins. We then discuss that, while no unique adipocyte surface protein might exist, how splicing, posttranslational modifications as well as protein/protein interactions can create enormous diversity at the cell surface that vastly expands the space of potentially unique epitopes and how these selective epitopes can be identified and targeted.

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.

Our understanding of white adipose tissue (WAT) biochemistry has evolved over the last few decades and it is now clear that WAT is not simply a site of energy storage, but rather a pliable endocrine organ demonstrating dynamic responsiveness to the effects of aerobic exercise. Similar to its established effects in skeletal muscle, aerobic exercise induces many biochemical adaptations in WAT including mitochondrial biogenesis and browning. While past research has focused on the regulation of these biochemical processes, there has been renewed interest as of late given the potential of harnessing WAT mitochondrial biogenesis and browning to treat obesity and type II diabetes. Unfortunately, despite increasing evidence that innumerable factors, both exercise induced and pharmacological, can elicit these biochemical adaptations in WAT, the underlying mechanisms remain poorly defined. Here, we begin with a historical account of our understanding of WAT exercise biochemistry before presenting detailed evidence in favour of an up-to-date model by which aerobic exercise induces mitochondrial biogenesis and browning in WAT. Specifically, we discuss how aerobic exercise induces increases in WAT lipolysis and re-esterification and how this could be a trigger that activates the cellular energy sensor 5′ AMP-activated protein kinase to mediate the induction of mitochondrial biogenesis and browning via the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator-1 alpha. While this review primarily focuses on mechanistic results from rodent studies special attention is given to the translation of these results, or lack thereof, to human physiology.

A central function of adipose tissue is in the management of systemic energy homeostasis that is achieved through the co-ordinated regulation of energy storage and mobilization, adipokine release, and immune functions. With the dramatic increase in the prevalence of obesity and obesity-related metabolic disease over the past 30 years, there has been extensive interest in targeting adipose tissue for therapeutic benefit. However, in order for this goal to be achieved it is essential to establish a comprehensive atlas of adipose tissue cellular composition and define mechanisms of intercellular communication that mediate pathologic and therapeutic responses. While traditional methods, such as fluorescence-activated cell sorting (FACS) and genetic lineage tracing, have greatly advanced the field, these approaches are inherently limited by the choice of markers and the ability to comprehensively identify and characterize dynamic interactions among stromal cells within the tissue microenvironment. Single cell RNA sequencing (scRNAseq) has emerged as a powerful tool for deconvolving cellular heterogeneity and holds promise for understanding the development and plasticity of adipose tissue under normal and pathological conditions. scRNAseq has recently been used to characterize adipose stem cell (ASC) populations and has provided new insights into subpopulations of macrophages that arise during anabolic and catabolic remodeling in white adipose tissue. The current review summarizes recent findings that use this technology to explore adipose tissue heterogeneity and plasticity.

Ileal interposition (IT) surgery delays the onset of diabetes in a rat model of type-2 diabetes (UCD-T2DM). Here, to gain a deeper understanding of the molecular events underlying the effects of IT surgery, we examined the changes in the proteome of four white adipose depots (retroperitoneal, mesenteric, inguinal, and epididymal) and plasma-free fatty acid profile in pre-diabetic rats 1.5 months following IT or sham surgery. The IT-mediated changes were exerted mainly in mesenteric fat and spanned from delayed adipocyte maturation to a neuroendocrine remodeling. Conversely, inguinal, retroperitoneal, and epididymal depots showed opposite trends consistent with increased adipocyte maturation and adipogenesis development prior to overt signs of diabetes, probably orchestrated by peroxisome proliferator-activated receptor gamma signaling and higher plasma n -6/ n -3 free fatty acid ratios. The resulting scenario suggests a targeted use of surgical strategies that seek to delay or improve diabetes in order to manipulate adipose depot-specific responses to maximize the duration and beneficial effects of the surgery.

The purpose of the present study was to determine the effects of prolonged hyperinsulinemia on mitochondrial respiration and uncoupling in distinct adipose tissue depots. Sixteen-week-old male mice were injected daily with placebo or insulin to induce an artificial hyperinsulinemia for 28 days. Following the treatment period, mitochondrial respiration and degree of uncoupling were determined in permeabilized perirenal, inguinal, and interscapular adipose tissue. White adipose tissue (WAT) mitochondria (inguinal and perirenal) respire at substantially lower rates compared with brown adipose tissue (BAT). Insulin treatment resulted in a significant reduction in mitochondrial respiration in inguinal WAT (iWAT) and interscapular BAT (iBAT), but not in perirenal WAT (pWAT). Furthermore, these changes were accompanied by an insulin-induced reduction in UCP-1 (uncoupling protein 1) and PGC-1α in iWAT and iBAT only, but not in pWAT or skeletal muscle. Compared with adipose tissue mitochondria in placebo conditions, adipose tissue from hyperinsulinemic mice manifested a site-specific reduction in mitochondrial respiration probably as a result of reduced uncoupling. These results may help explain weight gain so commonly seen with insulin treatment in type 2 diabetes mellitus.

Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function.

In mammals there are two types of adipocytes with opposing functions. Brown adipocytes are characterized by a high number of mitochondria and are specialized for heat production (thermogenesis), expressing thermogenic genes such as UCP1 (uncoupling protein 1). White adipocytes, on the other hand, store energy. Although many key regulators in the differentiation of white adipocytes have been established, our current knowledge on the same proteins in brown adipogenesis is lagging behind. One example is Pref-1 (pre-adipocyte factor-1), which maintains white pre-adipocytes in an undifferentiated state, but is only poorly characterized in the brown pre-adipocyte lineage. In this issue of the Biochemical Journal , Armengol et al. now shed new light on the role and regulation of Pref-1 in brown pre-adipocytes. First, Pref-1 specifically inhibits the thermogenic gene programme in brown pre-adipocytes. Secondly, they identified the transcription factor C/EBPδ (CCAAT/enhancer-binding protein δ) as a direct positive regulator of Pref-1 expression, whereas this protein does not fulfil this role in white adipogenesis. Taken together, these findings indicate that specific manipulation of brown adipocyte differentiation and/or function without interfering with their white adipocyte counterparts may be possible, which may open up new therapeutic ways to combat obesity-associated health problems.