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Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

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Volume 33, Issue 2

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White and beige adipocytes: are they metabolically distinct?

Diane M. Sepa-Kishi
  • Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, Canada
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/ Rolando B. Ceddia
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  • Muscle Health Research Centre, School of Kinesiology and Health Science, York University, 4700 Keele St., North York, Ontario, M3J 13P, Canada, Phone: 416-736-2100 (Ext. 77204), Fax: 416-736-5774
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Published Online: 2018-02-21 | DOI: https://doi.org/10.1515/hmbci-2018-0003

Abstract

The white adipose tissue (WAT) exhibits great plasticity and can undergo “browning” and acquire features of the brown adipose tissue (BAT), which takes place following cold exposure, chronic endurance exercise or β3-adrenergic stimulation. WAT that underwent browning is characterized by the presence of “beige” adipocytes, which are morphologically similar to brown adipocytes, express uncoupling protein 1 (UCP1) and are considered thermogenically competent. Thus, inducing a BAT-like phenotype in the WAT could promote energy dissipation within this depot, reducing the availability of substrate that would otherwise be stored in the WAT. Importantly, BAT in humans only represents a small proportion of total body mass, which limits the thermogenic capacity of this tissue. Therefore, browning of the WAT could significantly expand the energy-dissipating capacity of the organism and be of therapeutic value in the treatment of metabolic diseases. However, the question remains as to whether WAT indeed changes its metabolic profile from an essentially fat storage/release compartment to an energy dissipating compartment that functions much like BAT. Here, we discuss the differences with respect to thermogenic capacity and metabolic characteristics between white and beige adipocytes to determine whether the latter cells indeed significantly enhance their capacity to dissipate energy through UCP1-mediated mitochondrial uncoupling or by the activation of alternative UCP1-independent futile cycles.

Keywords: adipose tissue plasticity; beige adipocytes; brown adipose tissue; energy dissipation; fat oxidation; futile cycles; lipolysis; thermogenesis; UCP1; white adipose tissue

Introduction

Our knowledge of white adipose tissue (WAT) physiology has greatly advanced in the last few decades. The original idea of an energy storage compartment was modified by the discovery that the WAT also functions as an endocrine organ. In fact, there is now a long and expanding list of adipose-derived molecules (also known as adipokines) secreted by the WAT that can regulate the function of multiple organs and tissues in the body [1], [2]. It is now also well recognized that major functional differences exist between visceral (Vc) and subcutaneous (Sc) fat depots, with important implications for the physiopathology of obesity and its related metabolic disorders [3], [4], [5]. More recently, plasticity has become an important feature of the WAT due to its capacity to express, under specific conditions, components of the molecular machinery that confer unique metabolic characteristics to brown adipose tissue (BAT) [6], [7]. In fact, it has been recently demonstrated that the WAT tissue in rodents can acquire features of BAT upon cold exposure [8], chronic endurance exercise [9], [10], [11], [12] and β3-adrenergic stimulation [13]. This process has been referred to as “browning” of the WAT and became a topic of great interest among researchers due to its therapeutic potential for the treatment of metabolic diseases. When activated, BAT is well known for its ability to consume fat and glucose to produce heat [14]; thus, the induction of a BAT-like phenotype in WAT could promote energy dissipation within this tissue and reduce the availability of substrate that otherwise would be stored and expand adiposity. In humans, typical BAT is mainly localized in the supraclavicular, cervical and axillary regions, which collectively account for 66.6 ± 20% of the total BAT volume and 69.8 ± 19% of the total BAT activity [15]. The mediastinal, paraspinal and abdominal regions also contain BAT, but these compartments display lower metabolic activity upon cold exposure in comparison to supraclavicular, cervical and axillary BAT depots [15]. Based on 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT), it has been estimated that all human BAT depots combined represent ~1.5% of total body mass, and their ability to recruit and enhance metabolic activity upon cold exposure varies between different regions of the body, as well as between lean and obese subjects [15]. It has also been estimated that, if activated by cold to a similar extent as observed in cold-acclimated rat BAT, then 250 mL of young healthy human BAT could generate 115.5 kcal/day. A much higher contribution of BAT to whole-body energy expenditure (>520 kcal/day) is theoretically possible if all BAT depots were to be fully activated [15], although this is yet to be demonstrated. In fact, BAT can be found in specific depots in adult humans and it appears that only less than one-half of the fat in these depots is stimulated by acute cold exposure [15]. Thus, even though the thermogenic potential for typical BAT could lead to a significant increase in energy consumption, the size of this compartment may be a limiting factor to significantly elevate whole-body expenditure. Because the WAT accounts for a much higher proportion of total body weight (~20% in lean and 40% or more in obese individuals) [15] than classical BAT, browning of a relatively small amount of the WAT could largely expand the energy dissipating capacity of the organism. Ideally would be to recruit beige adipocytes in specific WAT depots to enhance the capacity of the organism for non-shivering thermogenesis. In this context, a question that has been asked is: can browning of the WAT indeed modify metabolism of a white adipocyte to make it function like a typical brown adipocyte? In other words, can the white adipocyte become less of an energy storage compartment and consume substrate to produce heat within itself? This is crucial to demonstrate that browning of the WAT can in fact have therapeutic value for obesity and its related metabolic disorders. Therefore, in this review we analyze differences with respect to thermogenic capacity and metabolic characteristics between white and beige adipocytes. The aim is to determine whether beige adipocytes indeed enhance their capacity to dissipate energy through uncoupling protein 1 (UCP1)-mediated mitochondrial uncoupling similarly to typical brown adipocytes.

Morphological and molecular characteristics of white and beige adipocytes

The WAT is a connective tissue composed of mature adipocytes and a stromal vascular fraction (SVF) that contains a variety of other cells including fibroblasts, endothelial cells, macrophages, pericytes, blood cells and preadipocyes [16], [17]. Even though adipocytes make up between 35 and 70% of total adipose mass in adults, they only account for 25% of the total cell population in the WAT. The SVF accounts for the remaining 75% [16], [17]. Typical white adipocytes are specialized to store excess energy and are characterized by the presence of one large lipid droplet (LD) (unilocular adipocyte) filled up with triglycerides (TAGs). The nucleus and mitochondria of the cell are pushed to the periphery by the presence of the large LD. White adipocytes contain a small number of mitochondria that are thin and elongated with randomly oriented cristae [18]. The lack in number and advanced structural development of the mitochondria results in white adipocytes having a very low oxidative capacity [18], which is compatible with the role of adipocytes primarily as energy storage compartments as opposed to cells that dissipate energy.

In contrast to white adipocytes, beige adipocytes express UCP1 and are characterized by the presence of multiple LDs (multilocular adipocyte) and more developed mitochondria that are densely filled with cristae [6], [19]. Mitochondria isolated from cold-exposed (browned) Sc inguinal (Ing) WAT also have significantly greater content of mitochondrial respiratory chain proteins compared to mitochondria isolated from control Sc Ing WAT [20]. Interestingly, the content of Complex I and IV in the browned Sc Ing WAT was significantly greater than that observed in activated BAT. Conversely, the content of Complex II, carnitine palmitoyl transferase 1 (CPT1) and UCP1 was significantly lower than that observed in activated BAT [20]. These findings provide evidence that mitochondria isolated from browned Sc Ing WAT acquire features that are typical of classical BAT mitochondria. However, some differences, particularly in substrate transport and UCP1 content, still remain lower in the Sc Ing WAT, which could affect substrate utilization in this tissue.

Origin of white and beige adipocytes

Though white and beige adipocytes differ morphologically and functionally, they have been shown to originate from one or more Myf5 cellular lineages [21]. This is in contrast to typical brown adipocytes that have been shown to originate from a Myf5+ muscle-like cellular lineage [21]. However, some beige cells have recently been shown to originate from a Myf5+ lineage [22], suggesting some heterogeneity within beige cells of certain WAT depots exists. This may help to explain why some WAT depots have a greater propensity to undergo browning than others. Indeed, the induction and appearance of beige adipocytes is depot specific with the Sc Ing depot being the most prone to browning compared to other Vc fat depots such as the epididymal fat [9], [11], [21], [23], [24], [25]. In addition to precursor cell lineage, this depot-specific propensity to browning may also be due to the ability of the depot to respond to various stimuli in order to induce the appearance of beige adipocytes. Browning is dependent on the transcriptional regulator PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16) [26]. PRDM16 exerts its effects through an interaction of its zinc finger (ZF1) domain with the MED1 subunit of the mediator coactivator complex. This leads to an increase in the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) and thyroid hormone receptor (TR) to increase the expression of Ucp1 [27], [28]. PRDM16 also enhances the expression of other proteins highly expressed in typical BAT such as cell death-inducing DFFA-like effector a (Cidea), cytochrome c oxidase subunit VIIIb (Cox8b) and peroxisome PPARγ coactivator 1 alpha (Pgc-1α) in beige adipocytes [21]. In addition to promoting the expression of browning genes, PRDM16 also plays an important role in repressing the expression of WAT-specific genes during differentiation [29], further promoting the brown adipocyte gene profile. In fact, the ability to recruit beige adipocytes is severely impaired in mice with WAT-specific deletion of Prdm16 or its cofactor Ehmt1. These mice also developed obesity, severe insulin resistance and hepatic steatosis on a high-fat (HF) diet [30]. These findings indicate that the ability to form beige adipocytes in the WAT is important for the regulation of whole-body glucose and fat metabolism.

Emergence of beige adipocytes in WAT: transdifferentiation vs. de novo adipogenesis

There has been some debate with respect to whether transdifferentiation or de novo adipogenesis lead to the formation of beige adipocytes. Transdifferentiation refers to the process by which pre-existing fully mature white adipocytes acquire the features of brown adipocytes. De novo adipogenesis implies the creation of an entirely new beige adipocyte within the WAT [12]. In support of the latter process, Wu et al. identified two distinct groups of progenitor cells from the Sc Ing WAT, one with a gene expression profile similar to WAT and another with a gene expression profile similar to classical BAT. When stimulated with cyclic AMP (cAMP), this latter group of progenitor cells enhanced Ucp1 expression [25]. These findings suggested that there exists in the Sc Ing WAT a particular set of progenitor cells that become beige adipocytes. This is further supported by data collected using an inducible mature adipocyte lineage-tracing system [31]. Using this model, Wang et al. were able to track adipogenesis in vivo and found that a large majority of newly emerging cold-induced beige adipocytes were the result of adipogenesis [31].

In support of transdifferentiation, studies in both mice and humans have shown that chronic sympathetic nervous system (SNS) stimulation increases the appearance of multilocular, UCP1-expressing adipocytes without increasing pre-adipocyte density [8], [32]. Furthermore, chronic SNS stimulation did not induce an increase in expression of Ki67 (a cell marker of proliferation) in humans [32] nor did it increase the expression of cyclin A1 (involved in cell cycling and proliferation) in the Sc Ing depot of mice [8]. Interestingly, researchers identified adipocytes following this stimulation that appeared to have characteristics in between that of white adipocytes and fully transdifferentiated brown adipocytes [8]. These intermediate adipocytes were termed paucilocular and were UCP1 positive. They were characterized by a large central LD along with some smaller LDs and a larger number of mitochondria with fully developed transverse cristae [8]. Visually, these intermediate cells appeared to be undergoing transdifferentiation into multilocular adipocytes. Interestingly, chronic β-adrenergic stimulation of these cells led to an increased expression of glycerol kinase (Gyk), the enzyme responsible for phosphorylating glycerol for incorporation into TAG and CIDEA, a protein that promotes LD enlargement [19]. These data provided evidence to propose a model of multilocular adipocyte development through the process of transdifferentiation [19]. Under the proposed model, chronic β-adrenergic stimulation would increase the release of fatty acids and glycerol. Increased expression of Gyk would promote the phosphorylation of glycerol and its use as a substrate for TAG re-esterification along with fatty acids. The newly synthesized TAG would form small LDs as observed in the paucilocular adipocytes. Finally, CIDEA would promote the enlargement of the small LDs and eventually lead to the multilocular appearance [19].

Substrate and energy metabolism in white and beige adipocytes

From a metabolic point of view, the main role of white adipocytes is to store chemical energy in the form of TAG, and release it as non-esterified fatty acids (NEFAs) when other tissues require energy. To carry out its normal function, the WAT uses glucose as the main substrate for energy production, as well as for the synthesis of intermediary molecules (e.g. glyceride-glycerol and glyceride-fatty acids) involved in WAT metabolism [33], [34]. It has been estimated that under basal conditions glucose is converted to the following main metabolites in isolated adipocytes: CO2 (25–30%), glyceride-glycerol (20–30%), glyceride-fatty acids (20–25%), pyruvate (10%), glycogen (2–3%) and lactate (1%). Upon stimulation with insulin, similar pathways of glucose metabolism are engaged, although the hierarchy of substrate partitioning in white adipocytes changes as follows: lactate > glyceride-fatty acids > CO2 > glyceride-glycerol = pyruvate [33]. Mitochondrial content [18], [35] and activity of enzymes involved in oxidative metabolism (e.g. citrate synthase, acyl CoA dehydrogenase and carnitine acetyltransferase) are relatively low in the WAT [36], [37]. In fact, proteome analysis revealed that mitochondria of white adipocytes support lipogenic functions instead of energy dissipation, although it also seems to exert a protective effect through the degradation of xenobiotics in the WAT. Conversely, at transcript and proteome levels, brown fat mitochondria more closely resemble muscle mitochondria, which support energy consumption in BAT [38].

Even though the rates of oxygen consumption and fatty acid oxidation in the WAT are relatively low in comparison to BAT, the flow of fatty acids in and out of the WAT can have an important contribution to the energy metabolism of the body. This is because in adipose tissue, stored TAG undergoes continuous, simultaneous synthesis and breakdown [39], [40]. Importantly, re-esterification of fatty acids seems to take place largely by an extracellular loop in which fatty acids released through lipolysis must first leave the adipocyte and then be taken up again. This extracellular loop is necessary due to a functional compartmentation of NEFAs within the adipocyte, which seems to prevent the access of lipolytically derived NEFAs to the enzymes of glycerolipid synthesis [41]. Importantly, fatty acid re-esterification increases proportionally with lipolysis [42], [43]. Re-esterification requires fatty acid acylation through a reaction that uses ATP and generates AMP, and two molecules of ATP are required for every molecule of fatty acid that is acylated. Because glycerol arising from lipolysis cannot be reutilized due to negligible GYK activity in the WAT [39], [40], fatty acid esterification in white adipocytes normally relies on glycerol 3-phosphate derived from the glycolytic and glyceroneogenic pathways [44]. These pathways also consume energy, so a total of 7–9 ATPs have been estimated to be required for the synthesis of a TAG molecule, depending on the origin of glycerol 3-phosphate [45], [46]. In fact, the energy required for this acylation reaction has been estimated to be the largest single drain of ATP in adipocytes stimulated by lipolytic hormones [47].

Classical unilocular white adipocytes lack UCP1 and are fully competent for ATP synthesis by oxidative phosphorylation. In fact, in mature white adipocytes, mitochondrial ATP synthesis is essential for major metabolic pathways (e.g. lipolysis, de novo FA synthesis, TAG synthesis, glyceroneogenesis and fatty acid re-esterification) [48]. The presence of UCP1 could affect the ability of a white adipocyte to produce ATP and disrupt these major metabolic pathways in the WAT. However, we still have limited knowledge of glucose and fat metabolism in beige adipocytes that contain UCP1. Data supporting a thermogenic function in brite/beige adipocytes originate mostly from morphological analysis (presence of multilocular LDs and mitochondrial remodeling) and molecular characteristics (expression of genes involved in mitochondrial biogenesis and Ucp1 mRNA expression). Whether these morphological and molecular changes ultimately cause an increase in substrate consumption at the WAT level to significantly affect adiposity remains debatable [49], [50]. This is because isolation of a homogenous cell population of primary beige adipocytes directly from WAT that underwent browning in sufficient quantities that are required for biochemical studies has proven to be challenging. Thus, studies using adipocytes have basically relied on the differentiation of stromal vascular cells (SVCs) extracted from Sc Ing fat depots into beige/brite adipocytes [49], [51]. However, these may not provide a true representation of the metabolic differences and physiological responses of classical brown and beige/brite adipocytes. Cultured SVCs are devoid of tissue-specific regulatory mechanisms that drive cell differentiation and metabolic adaptive responses. This is particularly relevant under conditions in which the organism is exposed to thermogenic challenges that promote specific adaptive metabolic responses in both BAT and WAT. In fact, differentiation of SVCs into adipocytes normally follows a protocol using a standard cocktail of drugs containing isobutylmethylxanthine, indomethacin, dexamethasone, insulin, triiodothyronine and rosiglitazone [52], [53]. This protocol induces lipid accumulation and the formation of adipocytes with multilocular appearance regardless of the tissue origin of the SVCs. Therefore, caution should be taken when translating findings from differentiated SVCs to in vivo metabolic changes that occur with WAT browning.

Fat depot-specific differences in oxidative capacity and substrate metabolism have also been reported to exist. Such differences could dictate the propensity of white adipocytes to turn into beige adipocytes under conditions that promote WAT browning. In fact, mitochondria from Sc Ing adipocytes that are more prone to acquiring a “brown-like” phenotype under conditions of cold exposure [8], chronic endurance exercise [9], [10], [11], [12] and β3-adrenergic stimulation [13], have been demonstrated to exhibit significantly higher respiratory capacity when compared to mitochondria from the epididymal WAT [54]. These differences in oxidative capacity were attributed to higher mitochondrial respiratory chain contents and mitochondrial capacity in Sc Ing than epididymal mouse white adipocytes. Furthermore, relatively short-term (1 week) HF feeding of these mice caused reduced oxidative capacity in both Sc Ing and epididymal adipocytes. However, this effect was much more pronounced in the latter than the former adipocytes [54]. These regional differences in mitochondrial oxidative capacity could be associated with higher metabolic risk for the development of glucose intolerance and dyslipidemia in Vc than Sc WAT.

Mitochondrial uncoupling, energy dissipation and fat metabolism in beige adipocytes

The expectation is that UCP1 positive beige adipocytes would exhibit elevated rates of substrate oxidation because of mitochondrial uncoupling. This is supported to some extent by in vitro studies conducted in mitochondria isolated from the Sc Ing fat depot of cold-acclimated 129Sv mice [20]. In these studies, the UCP1 protein content in mitochondria isolated from the Sc Ing fat depot almost reached the values of mitochondria in typical brown fat. Furthermore, Sc Ing mitochondria were thermogenically functional and exhibited UCP1-dependent thermogenesis. These mitochondria used lipid or carbohydrate as substrates and displayed guanosine diphosphate sensitivity, whereas in UCP1 knockout mice such thermogenic response was lost. UCP1-dependent oxygen consumption per gram of Sc Ing fat was estimated to be maximally one-fifth of interscapular BAT (iBAT). Additionally, the total quantitative contribution of all Sc Ing mitochondria was maximally one-third of all iBAT mitochondria [20]. Whether these in vitro findings with Sc Ing mitochondria translate into significant metabolic changes that consume fat and reduce adiposity in the long-term remains to be demonstrated.

We have found that adipocytes isolated from the Sc Ing and epididymal regions of male rats exposed to chronic endurance training enhance their capacity to oxidize fat, which is accompanied by reduced adiposity [9], [55]. Because chronic endurance training also increases UCP1 content in the Sc Ing fat depot [9], [10], [11] and HF diet-induced obesity reduces it [9], it is tempting to associate UCP1-mediated mitochondrial uncoupling with enhanced substrate consumption and reduced fat mass in beige adipocytes. Importantly, exercise increases oxidative capacity in both Sc Ing and epididymal WAT [55], although only in the former UCP1 content is increased [9]. This suggests that, despite browning of the Sc Ing WAT, exercise-induced enhancement of fatty acid oxidation in beige adipocytes may not necessarily be caused by UCP1-mediated mitochondrial uncoupling. Furthermore, exercise increases energy consumption, which on its own can lead to reduced adiposity through a process totally independent of UCP1-induced thermogenesis in beige adipocytes within the WAT. We have also detected increased mitochondrial density and fatty acid oxidation with reduced adipocyte area in epididymal, Sc Ing and retroperitoneal fat depots from rats treated for 4–8 weeks with the AMPK activator AICAR. Importantly, none of these metabolic alterations were accompanied by detectable levels of UCP1 in any of the fat depots studied [56]. Furthermore, AICAR-induced AMPK activation caused a potent anti-lipogenic effect by increasing the expression of PGC-1α, PPARα and PPARδ. It also suppressed fatty acid uptake and promoted oxidation of this substrate in rat white adipocytes [57]. These responses were accompanied by increased adipose triglyceride lipase (ATGL) content and fatty acid release [57]. Such findings indicate that WAT metabolism can be remodeled to promote fatty acid oxidation in adipocytes independently of UCP1 presence and mitochondrial uncoupling in white adipocytes.

Support for a UCP1-mediated fat-reducing effect has been provided by studies in which aP2-driven Ucp1 overexpression mitigated obesity induced by genetic or dietary factors in C57BL/6J mice. The obesity resistance, accompanied by mitochondrial uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of Ucp1 in white but not in brown fat [58]. However, age-dependent changes in aP2 promoter activity caused a decline in the content of transgenic UCP1 in all fat depots. In fact, in adult mice, the total content of transgenic UCP1 in white fat was reported not to exceed 2% of the UCP1 in iBAT [59]. This suggests that relatively small amounts of ectopic Ucp1 expression in WAT mitochondria can uncouple oxidative phosphorylation and reduce fat accumulation. However, the fat-reducing effects of WAT Ucp1 overexpression could also derive from the alteration of lipid metabolism in various fat depots, which is consistent with a marked reduction in fatty acid synthesis found in the Sc WAT of UCP1 transgenic mice [58]. This is also supported by studies in which forced Ucp1 expression in 3T3-L1 adipocytes reduced the total lipid accumulation in these cells by ~30% [60]. Furthermore, ectopic Ucp1 expression did not affect cytosolic glycerol-3-phosphate dehydrogenase activity and leptin production in 3T3-L1 adipocytes. However, it decreased glycerol output and increased glucose uptake, lactate production and the sensitivity of cellular ATP content to nutrient removal [60]. Surprisingly, oxygen consumption and β-oxidation were minimally affected in Ucp1 overexpressing 3T3-L1 adipocytes [60]. These findings suggest that the reduction in intracellular lipid by stable constitutive overexpression of Ucp1 reflects downregulation of fat synthesis rather than upregulation of fatty acid oxidation [60].

A potential mechanistic explanation for the reduced TAG accumulation in Ucp1-overexpressing adipocytes is that it inhibits ATP-dependent pyruvate carboxylase leading to a decrease in the mitochondrial pool of oxaloacetate and citrate. This would suppress the activity of the malate cycle, which in adipocytes supplies a significant amount of the NADPH needed for de novo fatty acid synthesis. It is also possible that the presence of UCP1 decreases ATP availability and phosphorylation efficiency, a condition that could divert carbon flux away from lipogenesis and toward fueling pathways such as glycolysis and the TCA cycle [61]. Importantly, in the normal fed state only a minute fraction of endogenous fatty acids are oxidized (~0.2%) in rat white adipocytes [62]. Therefore, it is likely that UCP1-mediated mitochondrial uncoupling in beige adipocytes enhances glycolysis and glucose oxidation in these cells. Enhanced glycolysis and glucose oxidation could provide a source of energy and intermediary compounds required for de novo fatty acid synthesis and re-esterification in beige adipocytes. In this context, UCP1-mediated enhanced glycolysis and tricarboxylic acid (TCA) cycle activity in beige adipocytes could significantly contribute to the removal of circulating glucose and favor whole-body glycemic control.

UCP1-mediated versus futile cycles in beige adipocyte thermogenesis

UCP1 is clearly a major determinant of non-shivering thermogenesis in BAT [14]. However, other UCP1-independent thermogenic mechanisms that operate in other peripheral tissues (e.g. skeletal muscle, liver and WAT) also seem to play important roles in the cold acclimation process [63], [64], [65], [66]. With respect to the WAT, even though the recruitment of beige adipocytes has been associated with mitochondrial uncoupling, the relevance of UCP1 to beige adipocyte thermogenesis has been challenged [63], [67]. In fact, alternative thermogenic energy-consuming pathways (e.g. TAG hydrolysis/lipogenesis futile cycle; activation of Na+-K+-ATPase, etc.) could also be induced under conditions of WAT browning [48], [49], [63]. These energy consuming pathways could ultimately lead to reduced adiposity independently of UCP1-mediated non-shivering thermogenesis (Figure 1).

Diagram depicting the proposed metabolic and morphological features that differentiate white and beige adipocytes in the WAT. Enhanced β3-adrenoreceptor (β3-AdR) stimulation leads to activation of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL), as well as to a marked increase in adipocyte lipolysis. Fatty acids (FA) released can be exported to the extracellular medium, undergo β-oxidation (β-ox), or be re-esterified into triacylglycerol (TAG). The latter pathway creates a thermogenic energy-consuming futile cycle of TAG hydrolysis and re-synthesis, which may facilitate the formation of multiple smaller lipid droplets (LDs) and change the appearance of the adipocyte from unilocular to multilocular. Beige adipocytes increase their UCP1 content; however, UCP1-mediated mitochondrial uncoupling seems to exert only a minor thermogenic contribution in these cells. In fact, several futile cycles including TAG hydrolysis/lipogenesis, creatine (Cr)/phosphocreatine (PCr) cycling and activation of ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2) seem to play a major role in energy dissipation in beige adipocytes. Glucose and FA are used in the tricarboxylic acid (TCA) cycle to produce energy to fuel multiple futile cycles, although glucose also contributes metabolic intermediates that are essential for FA re-esterification and de novo lipid synthesis (DNL) in beige adipocytes. DAG, Diacylglycerol; FA-CoA, fatty acyl-CoA; MAG, monoacylglycerol; G6P, glucose-6-phosphate; Gly, glycerol; Gly-P, glycerol phosphate; Glut, glucose transporter; Mito, mitochondria; OA, oxaloacetate; Pyr, pyruvate. ⇑ denotes increase and thick arrows indicate higher flow through the pathway.
Figure 1:

Diagram depicting the proposed metabolic and morphological features that differentiate white and beige adipocytes in the WAT. Enhanced β3-adrenoreceptor (β3-AdR) stimulation leads to activation of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL), as well as to a marked increase in adipocyte lipolysis. Fatty acids (FA) released can be exported to the extracellular medium, undergo β-oxidation (β-ox), or be re-esterified into triacylglycerol (TAG). The latter pathway creates a thermogenic energy-consuming futile cycle of TAG hydrolysis and re-synthesis, which may facilitate the formation of multiple smaller lipid droplets (LDs) and change the appearance of the adipocyte from unilocular to multilocular. Beige adipocytes increase their UCP1 content; however, UCP1-mediated mitochondrial uncoupling seems to exert only a minor thermogenic contribution in these cells. In fact, several futile cycles including TAG hydrolysis/lipogenesis, creatine (Cr)/phosphocreatine (PCr) cycling and activation of ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2) seem to play a major role in energy dissipation in beige adipocytes. Glucose and FA are used in the tricarboxylic acid (TCA) cycle to produce energy to fuel multiple futile cycles, although glucose also contributes metabolic intermediates that are essential for FA re-esterification and de novo lipid synthesis (DNL) in beige adipocytes.

DAG, Diacylglycerol; FA-CoA, fatty acyl-CoA; MAG, monoacylglycerol; G6P, glucose-6-phosphate; Gly, glycerol; Gly-P, glycerol phosphate; Glut, glucose transporter; Mito, mitochondria; OA, oxaloacetate; Pyr, pyruvate. ⇑ denotes increase and thick arrows indicate higher flow through the pathway.

More recently, it has been reported that cold exposure [68] and β3-adrenergic receptor stimulation [69] activate a UCP1-independent thermogenic mechanism involving creatine (Cr) cycling in mice Sc Ing beige adipocytes. These studies demonstrated that in UCP1 knock out mice genes involved in Cr metabolism are increased, whereas when Cr metabolism is disrupted the expression of classical thermogenic genes is elevated [68] (Figure 1). Thus, at least in mice, a compensatory relationship between UCP1- and Cr-dependent bioenergetics seem to exist. In this model, Cr is proposed to facilitate the regeneration of ADP through futile hydrolysis of phosphocreatine (PCr) [68]. The physiological relevance of this Cr-driven futile cycle for whole-body energy homeostasis has been demonstrated in mice with disrupted adipocyte Cr metabolism. This has been achieved through adipose tissue-specific deletion of glycine amidinotransferase (GATM), the rate-limiting enzyme of Cr biosynthesis. Mice lacking GATM in beige adipocytes exhibited blunted β3-adrenergic-induced activation of metabolic rate and were prone to diet-induced obesity [70]. This was attributed to the suppression of diet-induced thermogenesis, as mice lacking GATM failed to elevate energy expenditure in response to HF feeding [70].

Another UCP1-independent thermogenic mechanism involving the enhancement of ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2) has also been described in beige adipocytes [53] (Figure 1). Under conditions that increase intracellular Ca2+ flux (e.g. cold exposure and β-adrenergic stimulation) mouse Sc Ing adipocytes acquired a multilocular appearance, increased oxygen consumption rates (OCR) and enhanced glycolysis. These responses have been attributed to the activation of SERCA2b and RyR2 in beige adipocytes [53]. Because both Ca2+ and Cr cycling involve thermogenesis through breakdown and re-synthesis of ATP, both processes would be expected to converge to control UCP1-independent thermogenesis in beige adipocytes. Interestingly, when beige adipocytes lacking UCP1 (UCP1−/− cells) were depleted of Serca2b, OCR was reduced in these cells. However, when β-guanidinopropionic acid (β-GPA) was used to inhibit Cr transport in UCP1−/− cells, no reduction in OCR was observed [53], suggesting that these two processes are not directly connected. This is intriguing because both processes have been described as UCP1-independent thermogenic mechanisms either in beige adipocytes from UCP1 knock out mice [53] or in UCP1-negative Sc Ing mouse adipocytes [70]. Thus, one would expect that both processes would be operating simultaneously in these cells under conditions of cold-induced thermogenesis. Further research is required to reconcile these findings.

Expert opinion

Based on the accumulated information so far about browning of the WAT [19], [20], [53], [63], [68], [69], it appears that beige adipocytes can contribute to whole-body thermogenesis through several non-UCP1-dependent mechanisms (Figure 1). In fact, even though WAT browning confers some features of typical brown adipocytes (multilocular appearance and presence of UCP1) to beige adipocytes, it is the energy consuming futile cycles that seem to constitute the main thermogenic response of beige adipocyte within the WAT. Because these futile cycles are normally activated under conditions in which lipolysis is also enhanced (e.g. cold exposure and β3-aderenergic stimulation), a high rate of TAG breakdown/re-esterification also contributes to these non-UCP1-dependent thermogenic responses of beige adipocytes. Altogether, these futile cycles may lead to the formation of multiple small LDs that change the appearance of white adipocytes from unilocular to multilocular resembling classical brown adipocytes [19] (Figure 1). Thus, it appears that browning of the WAT forms beige adipocytes through remodeling the metabolism of white adipocytes to promote thermogenesis while still preserving the ability of the WAT to store and release fat.

Outlook

UCP1-mediated mitochondrial uncoupling seems to represent only a minor component of the energy dissipating system that operates in beige adipocytes. However, the collective set of metabolic alterations triggered by the activation of multiple futile cycles that take place with WAT browning can be of great therapeutic value. In this context, the increased expression of UCP1 in beige adipocytes may represent a reliable marker of the metabolic remodeling that takes place in the WAT. The UCP1 promoter contains response elements to cAMP and PPAR [14]. Thus, in addition to cold exposure, the induction of UCP1 positive beige adipocytes can also be accomplished through treatment with various pharmaceuticals such as rosiglitazone (a PPARγ agonist), cAMP, forskolin (a cAMP-inducing agent) or a β-adrenergic agonist [7], [24], [25]. Based on these discoveries, researchers have recently developed a microneedle patch containing nanoparticles of rosiglitazone or CL 316,243 (a β3-adrenergic receptor agonist) that when applied to the Ing region of mice resulted in an induction of browning genes type II iodothyronine deiodinase (Dio2), Cidea and Pgc-1α in the Sc Ing WAT [71]. Application of the microneedle patch also resulted in the appearance of multilocular adipocytes in the Sc Ing WAT and enhanced whole-body oxygen consumption [71]. Furthermore, treating diet-induced obese mice with the microneedle patches prevented weight gain and improved glucose tolerance [71]. These findings demonstrate the effect that drug-induced browning of the Sc Ing WAT can have on whole-body energy metabolism. This opens the possibility for the development of alternative therapeutic approaches that are designed to induce WAT browning in humans. It could promote changes in WAT metabolism with profound effects on whole-body energy expenditure, as well as in glucose and fat utilization. Such effects could be of great therapeutic value for the treatment of metabolic diseases.

Key points

  • Beige adipocytes are thermogenically competent.

  • Much less UCP1 is present in beige than brown adipocytes.

  • UCP1-mediated uncoupling seems to minimally affect fat oxidation in beige adipocytes.

  • UCP1-independent thermogenic mechanisms dissipate energy in beige adipocytes.

  • Browning of the WAT can favorably impact whole-body glycemic control.

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About the article

Received: 2018-01-08

Accepted: 2018-01-22

Published Online: 2018-02-21


Funding Source: Natural Sciences and Engineering Research Council of Canada

Award identifier / Grant number: RGPIN 2016-05358

Funding Source: Canada Foundation for Innovation

Funding Source: Ontario Research Foundation

Award identifier / Grant number: RBC

This research was funded by a Discovery Grant from the Natural Science and Engineering Research Council of Canada (NSERC) (RGPIN 2016-05358) and by infrastructure grants from the Canada Foundation for Innovation (CFI) and the Ontario Research Fund (ORF) awarded to RBC. DMSK was supported by the Elia Scholarship and the NSERC Alexander Graham Bell Canada Graduate Doctoral Scholarship.


Author Statement

Conflict of interest: The authors declare no conflict of interest.

Informed consent: Informed consent is not applicable.

Ethical approval: The conducted research is not related to either human or animals use.


Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 33, Issue 2, 20180003, ISSN (Online) 1868-1891, DOI: https://doi.org/10.1515/hmbci-2018-0003.

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