Abstract

Obesity is a metabolic condition usually accompanied by insulin resistance (IR), type 2 diabetes (T2D), and dyslipidaemia, which is characterised by excessive fat accumulation and related to white adipose tissue (WAT) dysfunction. Enlargement of WAT is associated with a transcriptional alteration of coding and non-coding RNAs (ncRNAs). For many years, big efforts have focused on understanding protein-coding RNAs and their involvement in the regulation of adipocyte physiology and subsequent role in obesity. However, diverse findings have suggested that a dysfunctional adipocyte phenotype in obesity might be also dependent on specific alterations in the expression pattern of ncRNAs, such as miRNAs. The aim of this review is to update current knowledge on the physiological roles of miRNAs and other ncRNAs in adipose tissue function and their potential impact on obesity. Therefore, we examined their regulatory role on specific WAT features: adipogenesis, adipokine secretion, inflammation, glucose metabolism, lipolysis, lipogenesis, hypoxia and WAT browning. MiRNAs can be released to body fluids and can be transported (free or inside microvesicles) to other organs, where they might trigger metabolic effects in distant tissues, thus opening new possibilities to a potential use of miRNAs as biomarkers for diagnosis, prognosis, and personalisation of obesity treatment. Understanding the role of miRNAs also opens the possibility of using these molecules on individualised dietary strategies for precision weight management. MiRNAs should be envisaged as a future therapeutic approach given that miRNA levels could be modulated by synthetic molecules (f.i. miRNA mimics and inhibitors) and/or specific nutrients or bioactive compounds.

Obesity and adipose tissue

Obesity is a worldwide epidemic that arises as a chronic long-term imbalance between calorie intake and energy expenditure. Despite nutritional interventions and physical education programmes, the prevalence of obesity is still increasing and ∼600 million people worldwide are expected to be obese by 2025, according to World Health Organisation (WHO) estimations [1]. Excessive accumulation of fat in the adipose tissue has been considered a major driver in the pathophysiology of obesity and associated features, such as cardiovascular disease (CVD), dyslipidaemias and type 2 diabetes (T2D) [2,3]. Adipose tissue is recognised as a pleiotropic tissue that plays a key role in the regulation of energy homoeostasis [4]. From a classical point of view, adipose tissue can be categorised into two types: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is a major energy storage organ that accumulates fat in form of triglycerides in specialised cells called adipocytes [5]. It is an important endocrine organ that produces and releases a number of bioactive molecules called adipokines [6], which participate in the regulation of metabolic functions at systemic level. On the other hand, BAT is specialised in burning lipids to dissipate energy in the form of heat, a process called thermogenesis. Brown adipocytes are characterised by central nucleus, small lipid droplets and high number of mitochondria as compared with white adipocytes.

Morphological changes in WAT upon obesity development lead to tissue dysfunction [7]. First, increased bloodstream free fatty acids (FFA) levels are considered an important factor mediating obesity-related disorders like insulin resistance (IR) and T2D. Secondly, increased fat mass leads to an alteration (mostly increase) in the secretory function of WAT. The disrupted secretory pattern of adipokines promotes a chronic low-grade inflammatory state in WAT, which has been also considered an underlying mechanism of IR, T2D and CVD [8,9]. In humans, WAT is located at different regions, which determines important functional differences, particularly concerning the secretory function [10]. Subcutaneous WAT (scWAT) is found under the skin and lipid accumulation at this region has been associated with a better metabolic profile as compared with other depots. On the other hand, visceral adipose tissue (vWAT), located within the abdominal cavity surrounding the main metabolic organs, has been linked to a higher incidence of metabolic complications, including IR, hyperlipidaemia and CVD [11].

Although sedentary lifestyle and unhealthy dietary habits are major drivers for obesity, there are other individual factors that might promote or prevent obesity development. The inter-individual susceptibility to obesity might rely on a combination of environmental, behavioural, genetic and epigenetic factors [12]. The term ‘epigenetics’ concerns dynamic cell-type changes that occur at transcriptional level that do not imply specific changes at DNA sequence. Epigenetic factors include changes in DNA methylation, histone modifications, chromatin status and non-coding RNAs (ncRNAs), including miRNAs, which can impact cell physiology and, therefore, affect susceptibility to certain diseases. In recent years, an intensive research has been carried out in order to study the epigenetic alterations associated with obesity and other metabolic disorders [13]. Among those, miRNAs have attracted particular interest due to their plasticity and high-potential regulatory actions [14]. Although some reports have reviewed the role of miRNAs in skeletal muscle in relation to obesity and metabolic diseases [15], this review critically examines their regulatory role from an ‘adipocentric’ point of view, by highlighting the role of miRNAs in adipose tissue and their eventual involvement in human obesity.

NcRNAs and miRNAs

NcRNAs are transcripts that lack protein-coding capacity which are present in all organisms and their expression levels correlate better with life complexity than protein-coding genes [16]. NcRNAs are subsequently classified according to their nucleotide length: long ncRNAs (lncRNAs) (>200 nts) and short ncRNAs [17]. Thus, miRNAs are short ncRNAs (20–22 nts) that act at post-transcriptional level to regulate gene expression [18]. They are key elements in cell transcriptional regulation that are estimated to regulate >60% of human mRNAs [18,19]. A particular miRNA signature confers specificity for transcriptional dynamics in a particular cell type and, thus, they have been considered as important mechanisms in the control of biological processes such as tissue development and cell function [20].

Although high-throughput methods and complex bioinformatics analyses have significantly contributed to the identification of new transcripts (including miRNAs), only few of them have been functionally characterised. Additionally, bioinformatics tools allow the prediction of potential binding sites of individual miRNAs to mRNA targets, although only few of them have been confirmed at experimental level [21,22].

In general terms, miRNAs bind directly to complementary base pairing of target mRNAs, usually at their 3′-UTR, and they down-regulate gene transcription. However, some studies have also shown that they can also bind to the 5′-UTR or even the coding region of the mature mRNA [23] and thus, regulate gene splicing [24]. Previous studies have determined a 6–7 bp length sequence to have perfect match and to be essential for functional interaction between miRNA and mRNA. This ‘seed’ sequence is usually located between nucleotides 2 and 8 of the mature strand of the miRNA. Recent studies have also identified other non-canonical interactions to be functionally relevant [25]. Indeed, new mechanisms of action for miRNAs have been also described. For instance, miRNAs can also up-regulate transcription: miRNAs can form triple helical structures (triplexes) that constitute a new mechanism by which miRNA can interact with gene promoter regions to modify gene transcription [26]. Additionally, miRNAs can also have specific nuclear functions: they have been described as an alternative mechanism of target recognition at promoter level [27]. Thus, on overall, the mechanisms of action of miRNAs to regulate transcription are diverse and include specific interactions miRNA–mRNA at different binding regions [28], targeting DNA sequences [29], increases in gene expression [30], regulation of miRNA localisation [31] as well as synergistic effects among other miRNAs [32] (Figure 1). Other non-canonical miRNA processing pathways and functions have been recently described and have been reviewed elsewhere [33].

Overview of ncRNAs and their role in the regulation of WAT functions

Figure 1
Overview of ncRNAs and their role in the regulation of WAT functions

(A) Main types of ncRNAs and mechanisms of action of miRNAs. MiRNAs are short ncRNAs that regulate gene transcription through different mechanisms. Moreover, they can be released within exosomes and can regulate cell functions in other cells/tissues (macrophages, liver, among others). Other ncRNAs such as piRNA (piwi-interacting RNAs), snoRNA (small nucleolar RNA), tRNAs can also be involved in the regulation of specific cell functions. (B) MiRNAs involved in the regulation of WAT functions with an altered expression pattern in obesity. MiRNAs regulate WAT function and their levels are altered in obesity. Specific miRNAs levels have been found to be up-regulated or down-regulated in obesity that eventually leads to WAT dysfunction. MiRNAs that have shown to influence WAT physiology and whose role is detailed in the present review are displayed in (B). Abbreviation: circRNA, circular RNA.

Figure 1
Overview of ncRNAs and their role in the regulation of WAT functions

(A) Main types of ncRNAs and mechanisms of action of miRNAs. MiRNAs are short ncRNAs that regulate gene transcription through different mechanisms. Moreover, they can be released within exosomes and can regulate cell functions in other cells/tissues (macrophages, liver, among others). Other ncRNAs such as piRNA (piwi-interacting RNAs), snoRNA (small nucleolar RNA), tRNAs can also be involved in the regulation of specific cell functions. (B) MiRNAs involved in the regulation of WAT functions with an altered expression pattern in obesity. MiRNAs regulate WAT function and their levels are altered in obesity. Specific miRNAs levels have been found to be up-regulated or down-regulated in obesity that eventually leads to WAT dysfunction. MiRNAs that have shown to influence WAT physiology and whose role is detailed in the present review are displayed in (B). Abbreviation: circRNA, circular RNA.

The fact that miRNAs can be secreted from cells has suggested a new and relevant networking role for these molecules since they might also constitute an important communication system between cells [34]. These extracellular miRNAs can be directly transferred, as naked RNAs, to target cells but normally, they are found inside small vesicles such as exosomes [34–36]. Consequently, exosomes cargo could constitute a potential regulatory factor on recipient cells. In this context, several studies have already shown the ability of secreted miRNA-containing exosomes to modulate cell and tissue functions [37,38]. However, there are still some caveats, such as the physiological impact of miRNAs, the relevance of miRNA/exosome transfer between cells and how this might affect health and disease. Of particular interest results their importance in metabolic diseases such as obesity. Although rodent models are an interesting approach to study obesity, some limitations exist due to species differences. Therefore, the current review will particularly focus on the studies carried out in humans.

Role of miRNAs in human obesity

Several studies have analysed differential expression of miRNAs in human adipose tissue between obese and lean subjects by high-throughput methods, such as microarrays [39–42] and, more recently, RNA-sequencing [43–45]. Initially, Ortega et al. [39] showed that 59 out of 799 miRNAs were significantly altered in scWAT in obese subjects as compared with lean. In addition to this, Martinelli et al. [41] evidenced that the expression of miR-519d was altered in scWAT of obese patients. However, an important caveat in these studies was that the functional role of the identified miRNAs was not established. Actually, only few studies have performed validation experiments to entirely address the biological relevance of those identified miRNAs to be differentially expressed between lean and obese individuals (complementary/additional studies with increased sample number, luciferase report assays for miRNA–mRNA interaction, among others). For example, the study performed by Arner et al. [40] encompassed analysis of differential miRNA expression in scWAT of lean and obese subjects. This research identified an altered pattern of 11 miRNAs that were expressed differentially in scWAT (miR-26a, -30c, -92a, -126, -143, -145,-193a/b, -652, let-7a/d) between lean and obese women, which was also complemented with functional characterisation experiments (physiological role of specific miRNAs) in human adipocytes [40].

Interestingly, some studies have correlated the expression levels of some miRNAs involved in obesity with anthropometric (i.e. body mass index (BMI)) and/or biochemical (i.e. glucose and insulin levels) parameters [46–48]. For instance, Ortega et al. [39] found that the expression levels of 17 miRNAs altered in obesity correlated with BMI and glycaemia. In parallel, Arner et al. [40] also correlated disrupted miRNA expression patterns with anthropometric measurements (weight, BMI, waist circumference, % body fat), IR (HOMA), and markers of adipocyte function. On the other hand, our group has identified three CpG sites located in coding regions of three miRNAs (miR-1203, miR-412 and miR-216a) as differentially methylated between obese and non-obese children, suggesting a role of miRNA epigenetic regulation in childhood obesity [49].

Another scenario to evaluate the role of miRNAs in adipose function in obesity involves weight loss. In this context, Kristensen et al. [42] identified a set of nine miRNAs whose expression was significantly altered after a 15-week weight loss programme that combined a hypocaloric diet and/or exercise. However, no changes were observed in any of the miRNA-predicted targets either at mRNA and/or protein level. García-Lacarte et al. [50] also reported that miR-612 and miR-1976 levels in white blood cells may be implicated in body weight loss by regulating the expression of TP53 and CD40. Interestingly, other studies from our group have identified specific miRNAs (Let-7b, miR-125b, miR-130a, miR-132-3p, miR-422) whose expression was altered in white blood cells after a dietary strategy for weight loss [51] and energy-restricted treatment (miR-935, miR-4772) [52].

Deep-RNA sequencing is the preferred tool to characterise miRNA profiles in WAT. However, to date, only few studies have used miRNA-seq to identify differentially expressed miRNAs in obesity and after weight loss. For instance, Armenise et al. [43] evaluated changes in transcriptional level in adipocytes from subjects that followed a low calorie diet for 6 months and found changes in lipid and glucose metabolism pathways. Additionally, they found a positive correlation between down-regulated genes and BMI and a negative one with Matsuda index (metabolic clearance rate during OGTT) [43]. Additionally, Tsiloulis et al. [44] have reported that miRNA expression profile in adipocytes is not apparently affected upon endurance exercise training in overweight men.

Although a significant number of miRNAs is expressed in WAT, only few of them seem to be altered in the obese condition. However, this fact raises the question of how a number of miRNAs or a specific ‘obesity miRNA pattern’ might impact adipose tissue biology and concomitant regulation. Additionally, several issues, such as the heterogeneity of subjects (wide ranges of BMI, body fat distribution), sample type and collection (adipose tissue compared with adipocytes; subcutaneous compared with visceral fat depots), makes it difficult to identify a particular miRNA and/or miRNA signature to be responsible for promoting/initiating the first steps of obesity. Of relative significance is the fact that seemingly, miRNAs found to be involved in the development of obesity are mainly down-regulated in obese WAT [40].

The relevance of miRNAs in adipose tissue function, metabolic control and energy balance has been a trending research topic in the last decade [53]. At WAT, miRNAs not only regulate adipose tissue formation (adipogenesis) but also adipocyte biology: endocrine function (adipokine secretion, inflammation) and glucose and lipid metabolism (diabetes and IR associated with obesity), including lipolysis, lipogenesis, WAT hypoxia and browning. For this reason, in this review, we examined the role of miRNAs in adipose tissue and their potential relationship with obesity (Figure 1).

Adipogenesis

Adipose tissue formation (adipogenesis) is a complex process whose main hallmark is the differentiation of pre-adipocytes into fully mature adipocytes [54]. Adipogenesis is tightly regulated by a complex array of transcription factors (peroxisome proliferator activated receptor (PPAR) γ (PPARγ), C/EBPs), hormones and other molecules, including long and short ncRNAs [54].

In adipose tissue, miRNAs are important regulators of the adipogenic process and the maintenance of specific metabolic functions [46,55] (Figure 1B). Interestingly, miRNAs up-regulated during adipogenesis were down-regulated in obesity [46], thus showing a reciprocal expression of miRNAs in adipogenesis and obesity [46,55]. For example, up-regulation of miRNA-519d has been linked to obesity [41], while it has also been reported to have a role in adipogenesis since miR-519d might bind to PPAR-α. These features suggest a role of this miRNA in adipocyte hypertrophy and on the regulation of lipid metabolism and fat mass in humans [56,57]. Complementary regulation of miRNAs during adipogenesis and obesity drives towards integrative methods and multilayered experimental designs in order to identify specific miRNAs altered in obesity. If miRNAs displaying a reciprocal regulation in obesity and adipogenesis are identified, a potential therapeutic approach could be envisaged to repair or restore altered miRNA levels in obesity and associated disorders [56].

Some other miRNAs have been shown to be involved in the control of adipogenesis. For instance, miR-143 modulates adipogenesis through regulation of the MAPK-ERK pathway [58]. MiR-377 is also considered a master mediator of adipogenesis: overexpression of this miRNA increases insulin sensitivity (though inhibition of SIRT1) and down-regulates adipocyte differentiation, which is mediated by a decrease in total lipid accumulation [59].

Several miRNAs regulate key points during the adipogenic process, including cell fate determination, clonal expansion and terminal differentiation [60]. For instance, up-regulation of miR-22 stimulates osteogenic differentiation [61] and miR-30 promotes thermogenesis and beige fat [62]. On the other hand, ectopic induction of Let-7 in 3T3-L1 adipocytes inhibited clonal differentiation [63] and on the contrary, stable miR-17-92 transfection of 3T3-L1 adipocytes resulted in accelerated differentiation and increased accumulation of lipids [64]. Other miRNAs have been described as positive (i.e. miR-21, -26b, -30, -103, -143, -148, -181a, -199a, -378) or negative regulators (i.e. let7, miR-22, -125a, -193a/b, -224) of terminal differentiation [44,63] as reviewed elsewhere [65]. Some of these miRNAs (f.i., Let-7 family, miR-22, -30d, -92a, among others) that have been shown to be involved in adipogenesis are also highly expressed in mature adipocytes [44], highlighting a potential role in adipocyte-related disorders like obesity. In this context, specific miRNAs involved in adipogenesis regulation have been reviewed more in detail [14,66].

Adipokine secretion and inflammation

Inflammation is a major hallmark in obesity. As adipose tissue expands, adipocytes become hypertrophied in order to store the excess energy and these hypertrophied adipocytes secrete excessive amounts of inflammatory molecules known as adipokines, such as monocyte chemoattractant protein 1 (MCP-1), IL-6 and/or tumour necrosis factor-α (TNF-α). These adipokines promote macrophage infiltration and alterations in adipocyte metabolism that, in turn, perpetuate a vicious circle of inflammatory factors, macrophage recruitment and impaired adipocyte function. In this context, miRNAs have been shown to regulate WAT inflammation in obesity [40,67].

Some of these miRNAs have been studied in order to decipher their potential functional role in human adipocytes and/or macrophages. For example, several miRNAs (f.i. miR-193b, -26a, -92a, -145) are known to regulate adipokine production, including MCP-1, TNF-α and adiponectin in WAT inflammation [14,40,68,69] (Figure 1B). In recent years, some reviews have been published on this topic [14]. Interestingly, the altered pattern of adipokines production observed in obesity constitutes a risk factor for the development of obesity-related malignancies such as different cancers [70]. Indeed, decreased adiponectin levels in obesity have been associated with gastrointestinal tumours [71] such as colorectal and prostate cancers [72] and female-specific neoplasies such as breast, cervix, ovaries and uterus [73].

Glucose metabolism: diabetes and IR

An interesting point is whether miRNA expression in obese WAT is also influenced by diabetes. Although some studies have evaluated the expression of miRNAs in WAT of diabetic obese patients, it is difficult to address specific miRNA changes in WAT due to alterations in glucose homoeostasis (diabetes) since diabetes is frequently linked to excessive fat mass (obesity) [14,39]. To this point, while miRNAs have been directly associated with diabetic features [74], it should be considered whether this is also related to excessive adiposity and/or whether functional characterisation is performed or involves adipose tissue or fat cells (Figure 1B). For instance, miR-143 and miR-103/107 have been related to impact insulin signalling and glucose metabolism by directly affecting WAT function [75,76]. On the other hand, miR-133 is known to regulate glucose metabolism in skeletal muscle [77,78] whereas miR-33 plays a key role in IR and obesity [79]. MiR-143-3p and miR-652-3p were also differentially expressed between insulin-resistant compared with insulin-sensitive obese women, increased insulin-stimulated lipogenesis in human differentiated adipocytes and affected several genes/proteins directly related to insulin signalling [74]. Positive associations (correlations) have also been observed between miR-24, -30 and -146a expression in abdominal WAT (obesity) and T2D [80]. Although the mechanism through which a specific miRNA signature determines diabetes development and/or IR still remains elusive. Interestingly, a more comprehensive review on this topic has also been published [81].

Lipolysis

Lipolysis consists of triglyceride breakdown in order to release FFA that could be used as energy substrate. Basal (spontaneous) adipocyte lipolysis is increased in obesity [82] while catecholamine-stimulated lipolysis is impaired. In this context, alterations in adipocyte lipolysis in obesity could also be mediated by specific miRNAs. For instance, overexpression of miR-30c, -652, -193b, -145 significantly increased basal lipolysis, while overexpression of miR-26a and Let-7d significantly inhibited lipolysis in human cultured adipocytes [68]. This feature was accompanied by substantial changes in the secretion of inflammatory adipokine TNF-α thus linking inflammation to lipolysis (Figure 1B). On the other hand, synthetic blocking of miR-10b was also able to suppress β-adrenergic-induced lipolysis in adipocytes [44]. MiR-124a has shown their ability to alter lipolysis by directly targeting lipolysis genes ATGL and CGI-58 [83]. Other studies have also explored the role of miRNAs on lipolysis in vivo by gain- or loss-of-function approaches. For instance, Zhang et al. [84], demonstrates that miR-378 transgenic mice developed metabolic disturbances due to elevated lipolysis and impaired glucose metabolism. Moreover, miR-378 overexpression led to an up-regulation on HSL and ATGL expression [84,85], demonstrating a role for this miRNA on the regulation of adipocyte lipolysis. Similarly, Lin et al. [86] demonstrated a functional role of miR-145 in the regulation of lipolysis both in vitro and in vivo. Finally, miR-33−/− mice showed decreased cytokine-stimulated lipolysis, suggesting a ‘more prone to obesity’ phenotype than corresponding wild-type counterparts.

Lipogenesis

Lipogenesis and lipid accumulation are tightly associated with adipocyte differentiation and adipogenesis though not restricted to this cell or tissue since hepatocytes/liver tissue/muscle also can accumulate lipids. In fact, specific studies are focused on the involvement of miRNAs in the regulation of lipid accumulation in both tissues: WAT/adipocytes and liver/hepatocytes.

In WAT, miR-22 has been reported to decrease lipid accumulation and TG storage by inhibiting adipocyte-specific genes involved in FA synthesis [87]. Additionally, overexpression of miR-24 down-regulated lipogenesis-related genes (FASN, ACLY, SCD1) and up-regulated some involved in cholesterol biosynthesis (HMGCR, SREBP2) [88]. These findings provide a direct link between lipid storage regulation by miRNAs and obesity. Increased expression of miR-204-5p during adipocyte differentiation led to increased number of Oil Red O positive cells (presence of lipid droplets), TG accumulation, and the expression of adipocyte differentiation markers, which seemed to be mediated by KLF3 inhibition, a negative regulator of adipogenesis [89]. Increased miR-199a-3p expression prevented lipid accumulation and adipogenic gene expression markers in brown adipocytes [90]. In liver, depletion of miR-7 led to increased lipid accumulation, suggesting that this miRNA could improve liver steatosis [91]. On the other hand, miR-1224-5p has been described as a positive regulator of lipid accumulation in liver and a promoter of hepatic lipogenesis: inhibition of this miRNA decreased cellular TG content in in vitro models (HepG2 and primary hepatocytes) by inhibiting AMPK1a [92] (Figure 1B).

Other studies on in vivo models (liver) have also shown that the absence of miR-22 prevented high-fat diet (HFD)-induced dyslipidaemia despite no changes in body weight, IR and glucose intolerance were observed [93]. Furthermore, miR-22 attenuated the increased expression of genes involved in HFD-induced lipogenesis and inflammation [93]. More recently, Guo et al. [94] demonstrated that lncRNA uc372 stimulated hepatic lipid accumulation by inhibiting miR-195/-4668 maturation. Inhibition of these miRNAs maturation led to relieve the suppression of lipid synthesis (ACC, FAS, SCD1) and lipid uptake (CD36) genes [94].

Other studies have examined how hepatosteatosis might induce changes in miRNA profile. In this context, miR-206 has been described as a ‘protective’ miRNA since it prevented hepatosteatosis and hyperglycaemia by stimulating insulin signalling and inhibiting lipogenesis (through Srebp1c) and lipid/glucose production [95]. In humans, Latorre et al. [96] identified 14 miRNAs related to obesity and NAFLD that were further investigated in human hepatocytes. They observed a decrease in miR-139-5p, -30b-5p, -122-5p, 422a, -146-5p in obese subjects with NAFLD [96]. In concordance with in vivo outcomes, palmitic acid, a saturated fatty acid that induces FA accumulation in hepatocytes, provoked an inhibition of miRNA expression (miR-139-5p, miR-30b-5p, miR-422a and miR-146a) in vitro that led to increased lipogenesis and fatty acid transport, and decreased glucose metabolism and fatty acid oxidation [96].

Hypoxia

Hypoxia has also been established as a mediator process of obesity-induced inflammation in adipose tissue [97]. Indeed, deleterious effects observed in obesity also rely on low oxygen levels in WAT [98]. The development of hypoxia in WAT could also be a cause or a consequence of an altered expression of miRNAs. In this context, some studies have explored the functional role of specific miRNAs in regulating angiogenesis within adipose tissue. For instance, Kang et al. [99] showed that adipose stem cells released multivesicles that enhance angiogenesis and miR-31 was identified to be a major causative factor for this effect [99]. MiR-31 was present in adipose-stem cell microvesicles and promoted endothelial cell migration and angiogenesis [100]. Additional experiments demonstrated that miRNA-31 regulated FIH1 mRNA (a transcriptional inhibitor of the hypoxia inducible factor HIF-1α) expression in HUVEC cells, linking miRNAs, hypoxia and adipose dysfunction. Other studies have explored the causative role of hypoxia in miRNA expression regulation. For example, Saad et al. [101] described that hypoxia increased the expression of miR-210 and decreased the expression of miR-34, -10a and -21 in adipose mesenchymal stem cells cultured under hypoxia and normoxia conditions [101]. Each miRNA targeted specific genes (i.e. VEGF and/or upstream pathway regulators) that ultimately boosted cell survival and amplified angiogenesis and anti-inflammatory functions of adipose-derived mesenchymal stem cells. Additionally, in 3T3-L1 adipocytes, hypoxia conditions up-regulated miR-27a/b expression, which inhibited PPAR-γ expression and led to impaired adipocyte differentiation [102].

The importance of miRNAs in hypoxia within the framework of obesity has also been linked to mitochondrial biogenesis and stimulation of WAT browning and thermogenesis [103]. In this context, miR-455 was demonstrated to target key adipogenic suppressors, such as the master hypoxia-inducible (transcriptional) factor HIF-1α, and to stimulate mitochondrial biogenesis and thermogenesis, two important features linked to the development of WAT browning (Figure 1B).

WAT browning

WAT browning has emerged as a promising strategy to combat obesity since it involves the appearance of inducible brown adipocytes (called beige or brite) in WAT [104]. In this context, some articles have reported that miRNAs may have an important role in the regulation of BAT function and stimulation of beiging or browning processes in WAT [105]. Stimulation of WAT browning by miRNAs relies on the ability to specifically regulate transcriptional modulators of brown adipocyte function [105]. In this context, positive and negative regulators of browning can be distinguished. Among the positive regulators, miR-30 has been shown to stimulate browning, since overexpression of this miRNA up-regulated thermogenic gene expression in subcutaneous white adipocytes [62] through inhibition of a thermogenic repressor (RIP-140) [106]. Additionally, miR-455 has been shown to stimulate browning through inhibition of adipogenic suppressors which in turn, led to activation of adipogenic markers PPAR-γ and PGC-1α [103] and stimulation of mitochondrial biogenesis through AMPK1a [103]. The effects of miRNAs on browning have also been shown in vivo since ectopic overexpression of specific miRNAs stimulated BAT thermogenesis and iWAT browning in several studies. For instance, miR-32 seems to have an active role in stimulating browning in vivo [107].

On the other hand, miRNAs can act as repressors of beiging/browning by directly inhibiting negative regulators of this process. Among the most relevant ones, miR-27 has been shown to specifically inhibit PPAR-γ and CEBP-α expression in adipocytes, which resulted in up-regulation of typical beige/brown-like markers like UCP-1, PRDM16 and PGC-1α [108]. Indeed, miR-27b is an upstream regulator of Prdm16 and thus, controls WAT browning. This finding suggests that the regulation of the browning process by miR-27 could also induce changes in adipose tissue depots and in body composition which potentially could be used as a target against obesity [109].

Similarly, miR-155 has been reported to down-regulate the adipogenic transcription factor CEBP-β and to promote stimulation of brown adipocyte differentiation both in vivo and in vitro [110]. Finally, in different independent studies, miRNA-133, -34a and -378 have been able to stimulate browning through inhibition of browning repressors [105,111–114] (Figure 1B).

Extracellular miRNAs in obesity and adipose tissue

Adipocytes can produce and release vesicles containing genetic material to communicate in a paracrine or endocrine manner with neighbouring cells within WAT or other distant tissues [115–117]. Much of this genetic material, such as miRNAs, is packaged into exosomes that can paracrine-/endocrinally modulate the function of surrounding cells within the adipose tissue, like preadipocytes, endothelial and immune cells, as well as other adipocytes [118,119]. Thus, miRNAs are not only present at intracellular level, but also they can be released from cells naked or within exosomes [35]. Thus, miRNA-containing exosomes can be isolated from biological fluids, including serum, plasma, saliva, sweat, urine and breast milk [120–123]. In this context, adipocyte-derived exosomes have been proposed to co-ordinate and regulate the function of cells in other tissues, such as hepatocytes [124] or peripheral blood monocytes [117], in an endocrine-like manner. Several studies have shown the ability of adipose-derived exosomes to be involved in the development and progression of obesity-associated inflammation. For instance, Zhao et al. [125] demonstrated that exosomes derived from adipose stem cells improved IR, decreased obesity, alleviated hepatic steatosis, reduced inflammation and induced WAT beiging in DIO mice. This study showed that adipose-derived stem cells produced exosomes that are eventually transferred into macrophages, thus demonstrating a novel exosome-mediated mechanism for adipose-derived stem cells–macrophages cross-talk. A study from our group also evidenced that exosomes from LPS-activated macrophages did not induce changes in adipogenesis, glucose uptake or fat storage, but stimulated changes in inflammation-related genes and expression of specific miRNAs (miR-530, -127, -143, -486) in adipocytes [126].

However, other studies have shown a causative role of exosomes in obesity incidence and obesity-related traits but have further attributed this effect to miRNAs contained in adipose-derived exosomes. For instance, Thomou et al. [127] showed that WAT produces circulating exosomal miRNAs (miR-419, -99a, -99b, -100) that have the ability to regulate gene expression (i.e. FGF21) in the liver. Similarly, Ying et al. [128] showed that WAT macrophages from obese mice secreted miRNA-containing exosomes that induced IR in lean mice and vice versa. These researchers identified miR-155 as a potential causative factor by directly targeting PPAR-γ [128].

Cells also produce and secrete miRNAs that are not within exosomes. These miRNAs have the ability to potentially regulate cell function in target cells [127,128]. Several studies have identified differences in the circulating miRNA profile between lean and obese subjects, although only a few have been functionally characterised. For instance, miR-17-5p and miR-132 circulating levels were found to be decreased in obesity, which was observed in parallel with accompanying miRNA expression levels in vWAT [129]. Associations between circulating miRNAs and the presence (or absence) of specific metabolic traits might allow considering miRNAs as biomarkers. In this context, it has been demonstrated that miR-27a is secreted into circulation by WAT and miRNA serum levels are related to obesity in obese children [130]. Moreover, WAT-released miR-27a promoted TG accumulation and induced IR in C2C12 cells through PPAR-γ repression [130]. However, a caveat would be to discriminate the cellular origin of secreted (circulating) miRNA levels (i.e. from WAT) in order to detect early physiological changes that could predict the development of obesity or other diseases and, thus, to potentiate the use of miRNAs as early diagnostic tools for metabolic disturbances.

In this context, it could be speculated that exosomes and miRNA production could be affected by WAT tissue changes and/or changes in body weight secondary to caloric restriction or nutritional intervention. For instance, Hubal et al. [131] showed that circulating adipocyte-derived exosomes were modified after gastric bypass and also correlated with post-surgery IR.

To date, it has not been fully elucidated whether a circulating (blood/plasma) miRNA signature might be linked to obesity, which could also be affected by genetic background, gender, age and/or other environmental factors [132,133]. However, there is some preliminary basis for considering of certain miRNAs as novel biomarkers for metabolic risk assessment [134], weight reduction process [52], and a classification system for obesity.

Finally, it has been suggested that the microbial excretion of outer-membrane vesicles containing miRNAs, might be one of the mechanisms by which gut microbiota dysbiosis can exert a metabolic impact on obesity and related comorbidities [135]. In any case, this researcher proposes a mutual modulation of miRNAs expression, both on the eukaryotic (host) and prokaryotic (gut microbes) side, as inducer of both metabolic diseases and gut microbiota dysbiosis [135].

Other ncRNAs (lncRNAs, circular RNAs) and their relevance in obesity and adipose tissue

In recent years, different types of ncRNAs have emerged as having important roles in cell biology. In addition to miRNAs, other species of ncRNAs such as lncRNAs (longer than 200 nts) and circular RNAs (circRNAs, which form a covalently closed continuous loop) have attracted particular interest. Providing their regulatory role in cell function, these ncRNAs are involved in the development of different diseases [136,137]. However, their influence in adipose tissue function and obesity is fairly unknown (Figure 1).

The total number of described and identified lncRNAs is rapidly increasing due to the development of high-throughput techniques such as RNA sequencing and complex bioinformatics tools. LncRNAs, in contrast with short ncRNAs, undergo post-transcriptional modifications (such as polyadenylation and splicing) although lack protein-coding capacity [138]. They can interact with DNA, RNA and proteins and participate in the regulation of epigenetic status and gene expression [139]. Several studies have shown that lncRNAs participate in tissue development, including adipogenesis [140,141] and have been reported to modulate adipose function in mouse models [142,143]. In this context, Sun et al. [140] identified ten lncRNAs that might regulate adipogenesis, lipid accumulation and mRNA expression of adipocyte markers, and described a pipeline for lncRNA identification and selection for functional analysis in adipocytes. The same group further characterised one of these lncRNAs (Firre), which interacted with the nuclear matrix factor hnRNP U to mediate chromosomal interaction for genes encoding adipogenic factors [144]. In a different study, these investigators characterised lnc-BATE1, which maintained brown gene programme and inhibited WAT-specific genes [143]. On the other hand, Zhao et al. [142] identified a lncRNA (Blnc1) that participated in the regulation of brown and beige adipocytes through physical interaction with transcription factor EBF2 and up-regulation of thermogenic genes. There is increasing interest in identifying novel lncRNAs with potential regulatory functions in adipogenesis and in maintaining adipose programme given their importance in obesity. So far, some lncRNAs contribute to transcriptional control of brown/beige genes [143], although newer studies will facilitate to further understand their function in adipocytes and their involvement in human obesity.

CircRNAs are ssRNAs that are produced from pre-mRNA splicing in eukaryotic cells [145]. As a result of this splicing, these species are closed (circular) RNA molecules that might act as post-transcriptional regulators [146]. Indeed, circRNAs might be involved in different homoeostatic functions such as miRNAs sponges (and thus, might serve as ‘titration’ molecules of miRNAs), regulation of transcription and gene interference [23]. Moreover, circRNAs have also been detected in blood [147], which opens a door for a future use as biomarkers [148]. Emerging evidence has linked some circRNAs to different diseases, suggesting a role in pathological conditions. For example, 489 circRNAs (particularly Hsa_circ_0054633) have been reported to be differentially expressed in the peripheral blood between healthy and T2D individuals [149]. However, the potential involvement of circRNAs in obesity remains still unclear [67].

Discovery of lncRNAs in human disease has also opened a promising field for their use as diagnostic and therapeutic agents. Since lncRNAs are expressed in a tissue-specific manner, identification of altered lncRNA patterns would allow future targeted treatments in diseases like obesity [150]. In this context, since lncRNAs can be easily detected as free nucleic acids in body fluids, there are already clinically approved tests for lncRNA detection for different types of cancer [151–153].

Clinical use and aplications: miRNAs as biomarkers and therapeutic agents in metabolic disorders

MiRNAs as biomarkers

Biomarkers with future application in obesity and metabolic diseases should be sensitive, robust, tissue-specific and independent of nutrient intake [154]. Plasma miRNAs are stable, including postprandial stage, which makes them attractive candidates to address or evaluate metabolic functions regardless of food intake. Additionally, the ideal potential of specific miRNA(s) as metabolic biomarker(s) should be verified in independent trials. For example, circulating miR-122 constitutes a potential biomarker for T2D, which is also supported by strong functional experiments [155]. Other authors have found associations between some circulating miRNA levels (decreased miR-103, -28, -29a, -9; increased 30a-5p, -150) and glycosylated haemoglobin, which could be of interest for predicting T2D development [156]. In this line, some reviews in the field have also addressed the potential role and use of miRNAs as biomarkers in diabetes and its complications [81,157]. Concerning obesity, Ortega et al. [134] found increased circulating levels of miR-140-5p, -142-3p and decreased levels of miR-532-5p, -125b, -15a, -520c-3p, -221, -130b and -423-5p in morbidly obese subjects. Ideally, potential miRNAs used as biomarkers should correlate to biochemical/metabolic parameters and/or anthropometric measurements (f.i. BMI, fat mass, fat distribution).

On the other hand, specificity should be mandatory in order to select good miRNAs as candidates to be novel biomarkers. This fact would mean that circulating (blood) biomarkers levels should reflect physiological changes at tissue level (f.i. adipose tissue) and preferably, their levels should correlate to biochemical parameters, as stated above. In this context, Heneghan et al. [129] reported lower levels of miR-17-5p and miR-132 in omental adipose tissue from obese subjects (compared with non-obese). Interestingly, circulating miRNAs levels reflected the expression in omental fat tissue, and miRNA expression (both in adipose tissue and blood) correlated with BMI, fasting glucose and glycosylated haemoglobin [129]. In this context, other authors have also reviewed the potential of miRNAs as early biomarkers in obesity, related metabolic and CVDs [158]. Additionally, providing that circulating adipokine levels, such as adiponectin, have been associated with obesity-related malignancies [72,73], miRNAs that specifically regulate adiponectin levels, could potentially be also examined as screening or prognosis biomarkers [159].

Interestingly, the selectivity of miRNAs also highlights their potential use for specific population groups (f.i. adults compared with children). In this context, circulating levels of 15 miRNAs (miR-486-5p, -486-3p, -221, -28-3p, -142-3p, -130b, -423-5p, -532-5p, -125b, -140-5p, -16, -328, -222, -363, -122) were found significantly associated with BMI among other anthropometric measurements, such as percentage of fat mass, waist/hip circumference and other clinical measures related to obesity. This information was found in a study including lean and obese children, which would be of interest to early identify children with potential metabolic disorders [132]. Additionally, specific miRNAs associate with metabolic features only in certain groups suggesting some limitations on their potential use as biomarkers in general population. Within this context, circulating levels of miR-33a and miR-33b were found to be up-regulated in plasma of hypercholesteraemic children, and miRNA levels were also positively correlated with total cholesterol, LDL, HDL/LDL, apolipoprotein B, CRP and glycaemia [160]. Similarly, these authors also found that circulating miR-200c was up-regulated in hypercholesteraemic paediatric patients, and its levels also correlated with miR-33a and miR-33b [161], showing a direct relationship between these miRNAs and metabolic traits. On the other hand, when obesity was combined with T2D, miR-15b levels were increased whereas miR-138, -376a and -503 were decreased [162] (Table 1). Thus, in summary, potential miRNAs that could be used as biomarkers should ideally, (i) correlate to biochemical/metabolic parameters and/or anthropometric measurements, (ii) reflect physiological changes at cell/tissue level (f.i. early stages of pathology development), (iii) be specific and remain stable, which could apply for certain population groups (f.i. children compared with adults).

Table 1
Summary of several miRNAs with potential interest as biomarkers in obesity and metabolic related traits
Biological sample miRNAs Condition References 
Omental adipose tissue ↓miR-17-5p, -132 Obesity (compared with non-obese) [129
Plasma ↓miR-532, -125b, -15a, -520-3p, -221, -130b and -423-5p
↑miR-140-5p, -142-3p 
Obesity (morbid) [134
Plasma ↓miR-221, -28-3p, -125b, -328
↑miR-486-5p, 486-3p, 142-3p, 130b and 423-5p, -532-5p, -140-5p, -16, -222, -363, -122 
Childhood obesity [132
Plasma ↑miR-33a, -33b, -200c Hypercholesterolaemia (paediatric) [160,161
Serum ↓miR-138 (Ob. and Diab.), -376a (Ob.) and -503 (Diab.)
↑miR-15b (Ob.) 
Obesity and T2D (diabetic compared with obese diabetic) [162
Plasma ↓miR-103, -28, 29a, -9
↑miR-30a-5p, -150 
Non-diabetic patients (some became diabetic) [156
Serum and plasma ↑miR-122 Metabolic syndrome or T2D [155
White blood cells ↓miR-155-3p
↑Let-7b 
Metabolic syndrome (8 wk dietary weight loss intervention) [51
Plasma ↑miR-935 in low responders (compared with high responders) at baseline and post-intervention
↑miR-221-3p, -223-3p (both groups) post-intervention
↑miR-140 in low responders post-intervention 
Overweight-obesity (16 wk dietary and exercise weight loss intervention) [163
Plasma ↑miR-140-5p, -142-3p, -222
↓miR-423-5p, -125b, -192, -195, -130b, -532-5p, -126 
T2D [164
Biological sample miRNAs Condition References 
Omental adipose tissue ↓miR-17-5p, -132 Obesity (compared with non-obese) [129
Plasma ↓miR-532, -125b, -15a, -520-3p, -221, -130b and -423-5p
↑miR-140-5p, -142-3p 
Obesity (morbid) [134
Plasma ↓miR-221, -28-3p, -125b, -328
↑miR-486-5p, 486-3p, 142-3p, 130b and 423-5p, -532-5p, -140-5p, -16, -222, -363, -122 
Childhood obesity [132
Plasma ↑miR-33a, -33b, -200c Hypercholesterolaemia (paediatric) [160,161
Serum ↓miR-138 (Ob. and Diab.), -376a (Ob.) and -503 (Diab.)
↑miR-15b (Ob.) 
Obesity and T2D (diabetic compared with obese diabetic) [162
Plasma ↓miR-103, -28, 29a, -9
↑miR-30a-5p, -150 
Non-diabetic patients (some became diabetic) [156
Serum and plasma ↑miR-122 Metabolic syndrome or T2D [155
White blood cells ↓miR-155-3p
↑Let-7b 
Metabolic syndrome (8 wk dietary weight loss intervention) [51
Plasma ↑miR-935 in low responders (compared with high responders) at baseline and post-intervention
↑miR-221-3p, -223-3p (both groups) post-intervention
↑miR-140 in low responders post-intervention 
Overweight-obesity (16 wk dietary and exercise weight loss intervention) [163
Plasma ↑miR-140-5p, -142-3p, -222
↓miR-423-5p, -125b, -192, -195, -130b, -532-5p, -126 
T2D [164

↑Up-regulated miRNAs; ↓Down-regulated miRNAs. Abbreviation: wk, week.

Another potential application of miRNAs as biomarkers is that they could also be helpful in the classification and management of obesity. Obesity ranking criteria might depend on specific levels of certain miRNAs that could indicate better or worse obesity prognosis (risk estimation) [134]. Additionally, miRNAs could be used as biomarkers of weight loss after caloric restriction [51,163,164] or bariatric surgery [134].

However, one of the caveats of the application of miRNAs as biomarkers relies on the lack of reproducibility in different studies. Available studies have shown some heterogeneity on the individual miRNAs that are differentially expressed at particular clinical settings. For instance, although there is consistent evidence that miR-221 may be down-regulated in obese individuals [134,165,166] its levels are increased upon surgery [134,167] and aerobic exercise [166,168]. On the other hand, there are conflicting data on the miRNAs that are down-regulated. Moreover, these apparent inconsistencies might be due to inter-individual differences (i.e. genetic background) and disparities in the methodology used in different studies, such as sample collection, processing, storage, RNA isolation and miRNA analysis. Uniformity in methodological procedures would help to drive definitive conclusions from different studies carried out in diverse approaches and would allow straightforward identification and use of miRNAs as potential biomarkers in obesity and metabolic related traits.

MiRNAs as therapeutic agents

Providing that miRNAs have the potential to regulate a number of genes, miRNA agonists (mimetics) and antagonists (inhibitors) could be interesting tools to repair or restore altered miRNAs in a particular tissue. In obesity context, functional characterisation of specific miRNA roles in adipose tissue might allow to develop adipose tissue-specific tools to correct obesity-linked dysfunction [14]. Indeed, some of the miRNAs shown to regulate adipose tissue function have been displayed in Figure 1B and thus, they could constitute potential therapeutic agents against obesity. If miRNA levels are down-regulated, the strategy would be to transfect synthetic miRNA mimetics (miRNA mimics) or plasmid/viral vectors [169]. At the moment, there are some clinical trials that are evaluating miRNA mimetics in other pathologies. For instance, a mimetic of miRNA-34a (which is inhibited in most cancers) is in phase I clinical trial [170]. Concretely, transplantation of miR-34a overexpressing adipose-derived stem cells has shown to enhance rat nerve regeneration [171] and to inhibit multiple myeloma cancer stem cell growth [172]. Moreover, new approaches for therapeutic use have been also assayed with promising results for cancer treatment: co-delivery of miR-34a and chemotherapeutic drugs into tumor cells for synergistic/optimal effects of anti-cancer treatment [173]. Thus, combination of multiple approaches using miRNAs could emerge for treatment of complex pathologies such as cancer or obesity.

On the other hand, if miRNAs are up-regulated, the therapeutic strategy would be to transfect-specific synthetic antisense miRNA/oligonucleotides, known as anti-miRs or antagomiRs that will compete for intracellular interaction with endogenous miRNAs/mRNAs. Most antagomiRs have a cholesterol fraction that allows efficient membrane diffusion and thus, can bind and inhibit intracellular miRNAs inducing a decrease in its levels in vivo [174]. Interestingly, physiological effects of miRNAs could involve different mechanisms of action (some have been described in Figure 1) and thus, the therapeutic approaches could vary accordingly.

Available evidence suggest that still there are no specific miRNA therapies to reduce fat mass in obesity, although technological advances would probably provide successful results in the line of research of metabolic diseases [57,174]. Esau et al. [175] potently inhibited miR-122 in liver with analogue 2′-O-MOE, which was accompanied by decreased plasma cholesterol levels and liver lipid content. Elmen et al. [176] used locked nucleic acids (LNAs; modified DNA oligonucleotides) to antagonise miR-122 in non-human primates, which led to an efficient, reversible and long-lasting reduction in miR-122 in liver with no toxicity evidence of histological modifications associated with LNA treatment [177,178]. In preliminary studies (mouse models), inhibition of miR-103/107 led to a significant reduction in fasting glucose and insulin levels and thus, might be potentially used for T2D treatment [76]. On the other hand, aberrant expression of lncRNAs can also be knocked down in vivo with oligonucleotides in a similar manner as described previously for miRNAs [179,180]. It should be stated that, as an alternative focus for miRNAs silencing, there is also a potential use of circRNAs (miRNA sponges) as inhibitors of miRNAs since they can scavenge multiple miRNAs. At the moment, there are some clinical trials (phase I) on-going. However, efficacy, specificity and toxicity are main challenges to optimise miRNA therapy and to consider the use of miRNAs as therapeutic agents in humans. Main challenges rely on manipulation of individual miRNAs within a target tissue such as adipose tissue. Since there are a number of potential mRNA targets, there is a considerable risk of secondary/adverse effects due to non-specific effects of the miRNA over target(s) mRNAs. Additionally, there is a potential risk for saturation of intracellular processing and/or degradation, which, in turn, might affect other miRNAs [181]. In conclusion, there are some unresolved questions around the potential therapeutic use of miRNAs and other ncRNAs, including gene selection, delivery, adverse effects, cellular context and efficacy of treatment, that must be properly addressed in clinical trials before ncRNAs might be used as therapeutic agents to treat obesity and its associated dysfunctions [55].

To circumvent this problem, one of the strategies that can be used is the modulation of the expression of specific miRNAs by bioactive compounds with anti-obesity properties. For example, our group has reported that 3 miRNAs were decreased and 13 were increased (miR-129, -328-5p, -539-5p, -1224, among most relevant) after resveratrol treatment in rats, and that the up-regulation of miR-539-5p was involved in the inhibition of de novo lipogenesis induced by resveratrol in WAT [182]. In a similar way, the reduction in liver steatosis induced by resveratrol in rats fed an obesogenic diet was mediated, at least in part, by the increase in CPT1-α protein expression and activity, via a decrease in miR-107-3p expression [183].

Clinical perspectives

  • Many miRNAs are differentially expressed in patients with obesity as compared with normal weight.

  • Several miRNAs and other small ncRNAs have an important role in adipose tissue metabolism, specifically in adipogenesis; adipokine secretion and inflammation; glucose metabolism; lipolysis; lipogenesis, hypoxia and WAT browning.

  • Circulating miRNAs (naked or within exosomes) secreted by WAT may regulate the metabolic function of distant organs and could potentially be used as biomarkers.

  • Secreted miRNAs could be used as potential biomarkers of diagnosis and prognosis of obesity, as well as predictors of body weight/fat mass reduction and/or specific dietary response, which allows an individualised approach on weight management.

  • MiRNAs illustrate a way to find new therapeutic targets through specific/individualised miRNA modulation (overexpression or inhibition) to ameliorate miRNA-dependent metabolic disorders, such as obesity and its related co-morbidities.

Acknowledgements

We thank the Spanish Government of Economy and Competitiveness (Nutrigenio project: AGL2013-45554-R and Obelex project: BFU2015-65937-R), Centro de Investigacion Biomédica en Red de Fisiopatología de la Obesidad y Nutricion (CIBERobn), Instituto de Investigación Sanitaria de Navarra (IdiSNA) and the Center for Nutrition Research of the University of Navarra.

Competing interests

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

Abbreviations

     
  • AMPK1α

    AMP-activated protein kinase 1-alpha

  •  
  • ATGL

    adipose triglyceride lipase

  •  
  • BAT

    brown adipose tissue

  •  
  • BMI

    body mass index

  •  
  • C/EBP

    CCAAT-enhancer-binding protein

  •  
  • circRNA

    circular RNA

  •  
  • CPT1-α

    carnitine palmitoyltransferase 1-alpha

  •  
  • CRP

    C-reactive protein

  •  
  • CVD

    cardiovascular disease

  •  
  • DIO

    diet-induced obesity

  •  
  • EBF2

    early B cell factor 2

  •  
  • ERK

    extracellular signal-regulated kinase

  •  
  • FA

    fatty acid

  •  
  • FFA

    free fatty acid

  •  
  • FGF21

    fibroblast growth factor 21

  •  
  • HDL/LDL

    high density lipoprotein/low density lipoprotein

  •  
  • HFD

    high-fat diet

  •  
  • hnRNU

    heterogeneous nuclear RNA

  •  
  • HOMA

    homeostatic model assessment

  •  
  • HSL

    hormone sensitive lipase

  •  
  • HUVEC

    human umbilical vein endothelial cells

  •  
  • IL-6

    interleukin-6

  •  
  • IR

    insulin resistance

  •  
  • KLF3

    Kruppel like factor 3

  •  
  • LNA

    locked nucleic acid

  •  
  • lnc-BATE1

    brown adipose tissue enriched long non-coding RNA 1

  •  
  • LncRNA

    long non-coding RNA

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MCP-1

    monocyte chemoattractant protein 1

  •  
  • ncRNA

    non-coding RNA

  •  
  • NAFLD

    non-alcoholic fatty liver disease

  •  
  • OGTT

    oral glucose tolerance test

  •  
  • PGC-1α

    peroxisome proliferator-activated receptor-gamma coactivator 1-alpha

  •  
  • PPAR

    peroxisome proliferator-activated receptor

  •  
  • PRDM16

    PR domain containing 16

  •  
  • RIP-140

    receptor-interacting protein 140

  •  
  • scWAT

    subcutaneous white adipose tissue

  •  
  • SIRT1

    sirtuin 1

  •  
  • TG

    triglyceride

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • T2D

    type 2 diabetes

  •  
  • UCP-1

    uncoupling protein-1

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • vWAT

    visceral white adipose tissue

  •  
  • WAT

    white adipose tissue

  •  
  • WHO

    World Health Organisation

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