Skip to content
Publicly Available Published by De Gruyter January 18, 2017

Browning of white adipose tissue: lessons from experimental models

  • Thereza Cristina Lonzetti Bargut , Vanessa Souza-Mello , Marcia Barbosa Aguila and Carlos Alberto Mandarim-de-Lacerda EMAIL logo


Beige or brite (brown-in-white) adipocytes are present in white adipose tissue (WAT) and have a white fat-like phenotype that when stimulated acquires a brown fat-like phenotype, leading to increased thermogenesis. This phenomenon is known as browning and is more likely to occur in subcutaneous fat depots. Browning involves the expression of many transcription factors, such as PR domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor (PPAR)-γ, and of uncoupling protein (UCP)-1, which is the hallmark of thermogenesis. Recent papers pointed that browning can occur in the WAT of humans, with beneficial metabolic effects. This fact indicates that these cells can be targeted to treat a range of diseases, with both pharmacological and nutritional activators. Pharmacological approaches to induce browning include the use of PPAR-α agonist, adrenergic receptor stimulation, thyroid hormone administration, irisin and FGF21 induction. Most of them act through the induction of PPAR-γ coactivator (PGC) 1-α and the consequent mitochondrial biogenesis and UCP1 induction. About the nutritional inducers, several compounds have been described with multiple mechanisms of action. Some of these activators include specific amino acids restriction, capsaicin, bile acids, Resveratrol, and retinoic acid. Besides that, some classes of lipids, as well as many plant extracts, have also been implicated in the browning of WAT. In conclusion, the discovery of browning in human WAT opens the possibility to target the adipose tissue to fight a range of diseases. Studies have arisen showing promising results and bringing new opportunities in thermogenesis and obesity control.


Beige or brite (brown-in-white) adipocytes were newly reported as adipocytes located in the white adipose tissue (WAT), but that resemble the brown adipocytes phenotype. In the basal state, brite adipocytes act as white adipocytes, but under the adequate stimulus they might transform into brown-like adipocytes, in a process called “browning” [1]. Recent studies indicated that human brown adipose tissue (BAT) is a brite adipocyte that acquired a brown-like phenotype [2] and that this conversion has beneficial metabolic consequences [3].

The subcutaneous depots of WAT are the most common location for browning as these adipocytes are predominantly smaller and have a greater potential to differentiate [4]. The ectopic expression of uncoupling protein 1 (UCP1) and PR domain containing 16 (PRDM16) are consistent to identify the presence of brite adipocytes within the white adipocytes [5, 6].

In the last years, a wide variety of pharmacological and nutritional compounds have been studied as agents of browning in humans and experimental models. In the present study, we focused on discussing recent in vitro and in vivo findings, though some problems in translating animals to human data exist [7].

Characterization of the brite/beige adipocyte

The adipose tissue is composed mainly by adipocytes, which are predominantly white adipocytes in the WAT, and brown adipocytes in the BAT. Consequently, WAT and BAT have different structures and biological roles. White adipocytes have a single large lipid droplet occupying most of the cell volume with few mitochondria, dislocating the nucleus peripherally. Brown adipocytes are polygonal cells containing several small lipid droplets (therefore, called multilocular adipose tissue), with a central nucleus surrounded by a clear cytoplasm and large amounts of mitochondria [8, 9] (Figure 1).

Figure 1: Adipocytes.White adipocytes have large lipid droplets, surrounded by little cytoplasm and a decentralized nucleus. Brown adipocytes have a polygonal appearance with multiple small lipid droplets and a centralized nucleus surrounded by a clear cytoplasm. Brite adipocytes are located in white adipose tissue resembling white adipocytes that under certain stimuli acquire a brown fat-like phenotype (tissues from C57BL/6 mice: light microscopy with hematoxylin and eosin stain or immunofluorescence and confocal microscopy marked with anti-uncoupling protein (UCP) 1 antibody). Same magnification, bar calibration=50 μm.
Figure 1:


White adipocytes have large lipid droplets, surrounded by little cytoplasm and a decentralized nucleus. Brown adipocytes have a polygonal appearance with multiple small lipid droplets and a centralized nucleus surrounded by a clear cytoplasm. Brite adipocytes are located in white adipose tissue resembling white adipocytes that under certain stimuli acquire a brown fat-like phenotype (tissues from C57BL/6 mice: light microscopy with hematoxylin and eosin stain or immunofluorescence and confocal microscopy marked with anti-uncoupling protein (UCP) 1 antibody). Same magnification, bar calibration=50 μm.

Also, WAT and BAT have different origins and progenitor cells, and many adipogenesis mediators [10]. WAT is found throughout the body, being divided into visceral (around organs – mesenteric, perigonadal, omental) and subcutaneous (under the skin – inguinal) depots. BAT is found in specific regions that comprises interscapular, subscapular, axillary, perirenal and periaortic regions in rodents, and cervical, supraclavicular, paravertebral, mediastinal and perirenal regions in humans [11]. Also, WAT represents the main energy reservoir of the body, while BAT is characterized by energy dissipation through thermogenesis. Both WAT and BAT function as endocrine tissues, signaling to other organs through adipokines (WAT) and batokines (BAT) [12, 13].

Brite adipocytes were newly reported as a type of adipocytes set in WAT, but resembling brown adipocytes phenotype. In the basal state, brite adipocytes act as white adipocytes, but under the adequate stimulus they might transform into brown-like adipocytes [1]. The origin of the brite adipocytes is still a matter of debate. When WAT is stimulated, a subset of cells may acquire a thermogenic phenotype (i.e. brown fat-like phenotype), without sharing the genetic markers of BAT, having a single developmental origin and molecular characteristics [14]. Indeed, brite adipocytes have a gene expression pattern different of WAT and BAT [1]. The key features of WAT, BAT and brite adipocytes are detailed in Table 1.

Table 1:

Comparisons between white, brown and “brite” adipose tissue.

OriginMyf5- cellsMyf5+ cellsMyf5- cells (differentiation or transdifferentiation)
FunctionEnergy storage and endocrine tissueThermogenesis and endocrine tissueAdaptive thermogenesis (under stimuli)
PhenotypeWhite-fat phenotypeBrown-fat phenotypeWhite-fat phenotype that acquires a brown-fat phenotype under stimuli
MitochondriaLowAbundantPresent (upon stimulation)
UCP-1 expressionAbsentPresentPresent (under stimuli)
Protein markersLPL, leptin, adiponectinPGC1α, PRDM16CD137, PRDM16, Tmem26
Pharmacological inductionPPAR agonists, renin-angiotensin system blockers, thiazolidinediones, among othersSympathomimetic drugs, thyroid hormones, thiazolidinediones, hormones like FGF21 and irisin, among othersAdrenergic receptor agonist, thyroid hormones, PPARα agonist, FGF21, irisin, BMP7, BMP8, AMPK activator, leptin, insulin, among others
Nutritional inductionn-3 PUFA, polyphenols, vitamin D, vitamin E, vitamin A, carotenoids, among othersPUFA, especially n-3 PUFA, bile acids, among othersAmino acid restriction, capsaicin, bile acids, n-3 PUFA, retinoic acid, among others
  1. AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; BMP, bone morphogenetic protein; CD137, cluster of differentiation 137; FGF21, fibroblast growth factor 21; LPL, lipoprotein lipase; Myf5, myogenic regulatory factor 5; PGC1alpha, PPAR coactivator 1 α; PPAR, peroxisome proliferator-activated receptor; PRDM16, PRD1-BF-1-RIZ1 homologous domain protein containing protein-16; PUFA, polyunsaturated fatty acids; Tmem26, transmembrane protein 26; UCP1, uncoupling protein 1; WAT, white adipose tissue.

It is relevant information that humans may have activation of BAT [15, 16]. Recent studies have indicated that human BAT is a brite adipocyte that was originally white, but, under stimulation acquired a brown-like phenotype [2]. Thus, human white adipocytes can be converted into brite adipocytes with beneficial metabolic consequences [3].

Molecular pathways related to browning and thermogenesis

The browning phenomenon gained relevance among scientific community when cold-activated thermogenic adipocytes were accidentally identified in patients subjected to positron emission tomography (PET) CT scans in Sweden [17]. These adipocytes, observed in the supraclavicular region, resembled the brite adipocytes seen in mouse models [18].

Before that observation, we believed that thermogenesis could not produce a significant body mass loss in adults [19]. However, in recent years brite adipocytes are considered a metabolic benefit: only 63 g of full-activated thermogenic adipocytes can burn approximately 4 kg of WAT a year (an obese adult – BMI>30 kg/m² – has 27 kg of WAT on average) [20, 21].

Subcutaneous adipocytes are more likely to undergo browning than visceral adipocytes because subcutaneous adipocytes are predominantly smaller and have a greater potential to differentiate [4]. The various stimuli capable of inducing browning are still in discussion. However, there is a consensus that the ectopic expression of UCP1 and PRDM16 is consistent to identify the presence of brite adipocytes within the white adipocytes [5, 6].

While UCP1 is the protein that performs thermogenesis itself [22], PRDM16 is a stimulus responsible for maintaining the brite adipocyte phenotype. Although PRDM16 is a common gene of BAT, brown adipocytes can perform thermogenesis even with a low expression of PRDM16. However, as recently shown, brite adipocytes may turn into white adipocytes again when the PRDM16 expression is low [23, 24]. Thus, browning is a reversible phenomenon and PRDM16 is a pivotal molecule when it comes to browning induction and thermogenic maintenance of the brite adipocytes [24].

Experimental evidence and clinical reports agree that sustained adrenergic stimulation is crucial to triggering the thermogenesis pathway [25]. An abundant innervation has always been attributed to BAT, but WAT is also significantly affected by this stimulus [26]. Viral tracking techniques have revealed an intricate sympathetic innervation in both visceral and subcutaneous WAT (sWAT) [27].

Beta-3 adrenergic receptor (β-3AR) is the main receptor involved in the thermogenesis pathway [15]. The p38 mitogen-activated protein kinase (p38 MAPK) stimulates the activating transcription factor 2 (ATF-2), driving the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1-α transcription [28]. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α) has got significant downstream effects promoting mitochondrial biogenesis and peroxisome proliferator-activated receptors (PPAR) activation [29]. PGC1-α activates nuclear respiratory factor 1 (NRF1), which communicates the nucleus with the mitochondrion and triggers mitochondrial replication by the activation of the mitochondrial transcription factor A (TFAM) [30].

UCP1, the thermogenesis effector, is in the inner mitochondrial membrane, indicating that mitochondrial biogenesis is essential to brite adipocytes induction. Moreover, mitochondria are widespread in the larger cytoplasm of the thermogenic-activated brite adipocytes [31, 32]. All PPAR isoforms (α, β, and γ) have been associated with UCP1 transcription [33, 34].

PPAR-γ orchestrates UCP1 transcription during brown adipocytes differentiation, but it is repressed in mature activated brown adipocytes [35]. After the differentiation, PPAR-α controls UCP1 levels in mature brown adipocytes [34]. Even though PPAR-γ plays a role in browning, the PPAR-α seems to be indispensable in activating the transcription of genes related to lipid oxidation carnitine palmitoyltransferase 1 (CPT1), which triggers β-oxidation and allows an unilocular adipocyte turn into a multilocular adipocyte [36].

As mentioned, PRDM16 is essential for brite adipocyte maintenance, but it also influences the browning process. Once again, PPAR-α controls the transcription of this essential gene, which interacts with PGC1-α to provide the machinery necessary for the transdifferentiation or differentiation of the brite adipocyte [29].

Today we accept that brite adipocytes stem from mature white adipocyte [low cluster of differentiation 137 (CD137), MYF5-cell progenitor], which under specific stimuli acquire a brown-like phenotype, or still from a beige preadipocyte (high CD137, MYF5-cell progenitor), which differentiates into a multilocular cell capable of performing thermogenesis. The latter originates from a lineage that differs from WAT [37, 38].

Irisin, a newly described adipokine, has a role in the differentiation of the preadipocyte in mature beige adipocyte [6], which express the cluster of differentiation (CD) 137, a beige-lineage selective cell surface protein. The PPAR-α stimulation is accompanied by a high irisin gene level. Also, irisin acts via PGC1-α to enhance UCP1 expression, which is also a PPAR-α target gene, maximizing thermogenesis [39, 40]. The crosstalk between different pathways controlled by PPAR-α suggests that PPAR-α might orchestrate thermogenesis in the mature brite adipocytes and has potential to trigger Browning, though the way (transdifferentiation or differentiation) remains to be unraveled. Figure 2 summarizes the main pathways outlined in this section.

Figure 2: Pathways related to thermogenesis and browning.Beta 3-adrenergic receptor stimulation leads to PGC1 induction, which drives PPAR activation and mitochondrial biogenesis. These stimuli allow the white adipocyte to acquire brown adipocyte features in an event called “browning”, where the enhanced expression of PRDM16 and UCP1 are considered as hallmarks for thermogenic activity in the new beige/brite adipocyte (A). An interaction between PPAR-α and irisin stimulates browning as it favors UCP1 and PRDM16 great expressions. Conversely, under reduced expression of PRDM16 and UCP1, the brite adipocyte can turn in a white adipocyte, showing the reversible nature of browning phenomenon (B).
Figure 2:

Pathways related to thermogenesis and browning.

Beta 3-adrenergic receptor stimulation leads to PGC1 induction, which drives PPAR activation and mitochondrial biogenesis. These stimuli allow the white adipocyte to acquire brown adipocyte features in an event called “browning”, where the enhanced expression of PRDM16 and UCP1 are considered as hallmarks for thermogenic activity in the new beige/brite adipocyte (A). An interaction between PPAR-α and irisin stimulates browning as it favors UCP1 and PRDM16 great expressions. Conversely, under reduced expression of PRDM16 and UCP1, the brite adipocyte can turn in a white adipocyte, showing the reversible nature of browning phenomenon (B).

Pharmacological induction of Browning

Many pharmacological agents have been linked to a facilitation of brite/beige phenotype acquisition by white adipocytes [41]. Despite being a recent issue, we aimed to describe in this section the main pharmacological approaches related to WAT browning as well as the endogenous signals activated by each one of them.

An adrenergic stimulation is essential to trigger thermogenesis. Thus, many strategies to induce WAT browning, converge to the stimulation of β-3AR, with the consequent enhanced lipolysis, which is followed by a greater capacity for lipid oxidation and thermogenesis in the mitochondria [42]. Chronic treatment with β-3AR agonist induces ectopic UCP1 expression in WAT coupled with a significant mitochondrial enhancement. Also, a moderate elevation of β-3AR expression is associated with a significant body mass loss due to WAT browning [43], while a β-3AR depletion in knockout mice reduce WAT multilocular adipocytes and UCP1 expression [42]. The proposed mechanisms are related to the cyclic adenosine monophosphate (c-AMP)-dependent protein kinase A (PKA) activation and the activation of its target gene p38 MAPK with downstream effects such as PGC1-α and PPAR-α activation [44].

A selective PPAR-α activation by fenofibrate makes WAT browning in a diet-induced obesity model [45, 46], with a consequent reduction in the body mass and hepatic steatosis, implying that thermogenesis can metabolize the excessive free fatty acids from lipolysis, mitigating their deposition as fat droplets in the liver [47, 48].

Along with PPAR agonists, the chronic use of AMP-activated protein kinase (AMPK) activators ended up in increased energy expenditure and mitochondrial biogenesis, without a great impact on ectopic UCP1 expression [49]. Although AMPK activators potentially may enhance PGC1-α, the effects on WAT browning is controversial and seem to be species-dependent. The increased UCP1 expression in gonadal white adipocytes has been identified in rats under a long-term treatment with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) [49].

Irisin might explain the reason why AMPK activators do not always produce WAT browning. This adipokine relies on PGC1-α to trigger WAT browning [1, 39]. Moderate augmentation in irisin level complies with ectopic expression of UCP1 in WAT, followed by obesity and insulin resistance tackling [39]. It seems that the enhanced PPAR-α expression coupled with high levels of irisin acts as an important surrogate of WAT browning [39, 46]. Of note, exercise seems to stimulate WAT browning through an irisin-dependent pathway as irisin is similarly secreted by the skeletal muscles (being also classified as a myokine) [39, 40]. However, it is likely that muscle secretion does not influence WAT browning significantly as sweat production does [50].

The FGF21 is a metabolic regulator. It is secreted predominantly by the liver, but is also secreted by BAT and sWAT after a suitable stimulation (cold exposure or adrenergic stimulation) [51, 52]. Paracrine and autocrine signals induce UCP1 and other thermogenic genes through a PGC-α-dependent mechanism in FGF21-treated mice, being more relevant in sWAT than in BAT [52]. A possible interaction with irisin is thought to cause increased oxygen consumption by adipocytes, which might explain the reduced fat depots following FGF21 treatment [51].

Another synergism happens between natriuretic peptides and β-3AR stimulation. Formerly regarded as a hormone involved in blood pressure regulation through the salt excretion control and renin-angiotensin system modulation, the atrial natriuretic peptide (ANP) is released after exercise and yields increased UCP1 gene and protein levels in human adipocytes in vitro [53]. Energy uncoupling increase by ANP does not rely on adrenergic stimulation, but is maximized by its [27]. A significant overlapping between PKA and cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG) downstream effects has been described and this observation is possibly the reason why ANP stimulates lipolysis in a similar degree of adrenergic stimulation [54].

The nicotine is strongly associated with a decrease in body mass, a small food intake, an increase of both lipolysis and energy expenditure [55]. However, cigarette smoking did not induce browning in sWAT [56], whereas treatment with nicotine caused increased UCP1 gene levels by multilocular adipocytes in WAT [57].

Bone morphogenetic proteins (BMPs) play different roles in adipocyte differentiation and physiology [58]. BMP-7 is associated with enhanced lipid accumulation, UCP1 expression and mitochondrial density in brown adipocytes [59], and browning of murine and human sWAT in vitro [60]. Also, BMP-7 stimulates PRDM16, which, in turn, induces PGC1-α and its downstream effects related to mitochondrial biogenesis and UCP1 activity [61].

BMP-8 acts centrally to intensify the adrenergic signaling, an important triggering stimulus of both browning and thermogenesis [62]. Increased BMP-8 gene levels were detected in obese mice treated with PPAR-α agonist, and BMP-8 augmentation was proportional to β-3AR and the UCP-1 rise [46]. Conversely, mice lacking BMP-8 showed a greater susceptibility to diet-induced obesity [62].

The adipoinsular axis refers to the interplay between insulin and leptin to control appetite and glucose handling [63]. Insulin and leptin function synergistically in hypothalamic neurons to promote WAT browning. The deletion of tyrosine protein phosphatase 1B (PTP1B) and tyrosine protein phosphatase nonreceptor type 2 (TCPTP) augment insulin and leptin signaling in POMC neurons, which a greater energy expenditure and brite adipocytes in WAT [64]. The infusion of leptin and insulin into the central nervous system yielded activated POMC neurons and put forward a central control of WAT browning [64, 65]. Also, the thyroid hormone has an influence on WAT plasticity. After treatment with T3 (triiodothyronine) human adipocytes differentiate from multipotent adipose-derived stem cells, acquiring a multilocular aspect, enhancing mitochondrial density and UCP1 expression [66].

Nutritional induction of Browning

Nutritional elements have effects centrally in the brain, like some amino acids restriction and malnutrition, and capsaicin. Capsaicin is an ingredient of hot pepper, widely used as a spice in food products. Capsaicin is recognized as a target to treat obesity and adipogenesis because it binds to the TRPV1 protein activating neurons, increasing catecholamine secretion and thermogenesis. Capsaicin gave to rats fed a high-fat diet led to an increased UCP1 mRNA expression in WAT [67]. Low doses of capsaicin induce a brite phenotype in differentiating 3T3-L1 preadipocytes [68]. Also, Capsaicin activates TRPV1 channels, promoting browning of WAT that counteracts obesity in mice [69].

Dietary methionine restriction induces an increase in energy expenditure with a rise in UCP1 expression in WAT [70], even in ob/ob mice [71]. The dietary methionine restriction appears to increase UCP1 and energy expenditure through increased nervous system stimulation of adipose tissue [72]. In maternal rodent undernutrition, there is an enhancement of UCP1 gene expression in WAT of male offspring until postnatal day 21, but this effect is lost after weaning [73].

Fucoxanthin, a carotenoid from edible seaweeds can upregulate UCP1 expression in mice WAT [74], which could partially counteract obesity in KK-Ay mice [75]. These beneficial effects of fucoxanthin in WAT against obesity appear to be related to increases in the expression of β-3AR [76].

In diet-induced obesity in mice supplemented with the flavonoid luteolin, there is increased energy expenditure associated with upregulation of thermogenic genes (e.g. UCP1, PGC1-α, PPAR-α, among others) in sWAT. The effects of luteolin are mediated by AMPK/PGC1-α signaling since AMPK inhibition ablated the effects [77].

Another potential nutrient is the amino acid Citrulline. Citrulline treatment of lean and diet-induced obese mice upregulated UCP1, PPAR-α, and PGC1-α in WAT, resulting in elevated thermogenesis accompanied by a reduced body fat mass [78].

The role of bile acids in upregulating thermogenesis was recently described. Bile acids are essential for lipid absorption in the intestine and may have an involvement in lipid metabolism [79]. There are effects of bile acids (i.e. cholic acid and chenodeoxycholic acid) on BAT increasing energy expenditure and inducting UCP1-mediated thermogenesis [79, 80]. In WAT, stimulation of a bile acid sensor (farnesoid X receptor, FXR) by its agonist (FXR agonist fexaramine) promotes browning, opening a new therapeutic field [81]. At least in BAT, the mechanism of action of bile acid is mediated by G protein-coupled receptor 5 (TGR5) [79].

Another well-studied browning inducer is Resveratrol, a polyphenol present in berries and grapes, among others. Resveratrol supplemented to mouse embryonic fibroblast-derived adipocytes elevated mRNA expression of UCP1 [82]. In vitro, Resveratrol increased gene and protein expressions of brown fat markers including UCP1, PRDM16, and PGC1-α in adipocytes [83, 84]. Resveratrol induces browning of WAT with UCP1 upregulation and enhancement of fatty acid oxidation in vivo, possibly by activating AMPK [83].

Some types of lipids [n-3 polyunsaturated fatty acids – (PUFA)] have the potential to induce browning. The n-3 PUFA is related to a wide variety of beneficial effects in many diseases as immune, inflammatory, and cardiovascular diseases, besides cancer, obesity, and the metabolic syndrome [85]. The eicosapentaenoic acid (EPA, one of the bioactive n-3 PUFA) can promote browning of subcutaneous adipocytes [86]. In accordance, fish oil (rich in n-3 PUFA) given to mice induces browning of subcutaneous WAT, with the presence of several gene markers, including CD137 that is exclusive of brite cells [87].

Also, the conjugated linoleic acid (CLA) enhances UCP1 in obese ob/ob mice independently of increases in β-3AR, acting against fat deposition [88]. The CLA-induced UCP1 expression in WAT contributes to obesity reversion in a mechanism independent of PPAR-α [89]. The synthetic fatty acid 2-hydroxyoleic acid given to rats resulted in increased UCP1 expression in WAT, inducing body mass and fat mass losses [90].

The retinoic acid is the carboxylic acid form of vitamin A with action on several nuclear receptors. All-trans retinoic acid induces UCP1 expression through its binding to the retinoic acid receptor in white rodent adipocytes, independently of PGC1-α [91]. In obese mice, treatment with all-trans retinoic acid induces UCP1 expression, through both retinoic acid receptor and PPAR-β/ƛ [92]. All-trans retinoic acid increases mice multilocular adipocytes in inguinal WAT, suggesting browning with concomitant increases in mRNA expression of UCP1, PPAR-α, PGC1-α, CPT-1, among others [93]. Also, mouse embryonic fibroblast-derived adipocytes exposure to all-trans retinoic acid showed enhancement of UCP1 mRNA and protein expressions accompanied by increases in PRDM16 [94].

Other nutrients, including plant extracts, may have potential in inducing browning. For example, thymol (5-methyl-2-isopropylphenol), a natural monoterpene phenolic constituent of essential oils produced by plants such as thyme species, induces browning of 3T3-L1 adipocytes, enhancing the expression of many brown fat specific markers [95]. On a diet-induced obese model, β-lapachone (a naphthoquinone) stimulates the browning of WAT, with higher UCP1 expression and lower body mass [96]. The black soybean seed coat extract, a polyphenol-rich food material, also elevates UCP1 protein expression in sWAT and reduces body mass with regularization of glucose intolerance [97]. Berberine, a naturally occurring plant alkaloid present in many Chinese herbal medicines, activates thermogenesis in WAT of db/db mice, with the browning of this tissue through AMPK and PGC1-α signaling [98]. Lastly, artepillin C, a typical Brazilian Propolis-derived component, induces brown-like adipocytes in mouse primary inguinal WAT-derived adipocytes due to activation of PPAR-γ and PRDM16 stabilization, independent of β3-adrenergic signaling [99].

Other metabolites may be added to the list of browning inducers. Among them, both lactate and the ketone body β-hydroxybutyrate were shown to increase UCP1 expression in murine WAT cells, therefore promoting browning, possibly as a mechanism to alleviate redox pressure [100]. Besides that, rats given inorganic nitrate in drinking water showed expression of the brown adipocytes genes and proteins and β-oxidation genes in WAT, increasing oxygen consumption. The mechanism of browning appears to be related to the reduction of nitrate to nitric oxide that in turns increase cGMP, activating PKG and, consequently, increasing the expression of PGC1-α and other key browning genes [101].

Cold adaptation: energy dissipation, non-shivering thermogenesis

The cold-induced thermogenesis can be either a non-shivering thermogenesis (NST) or a shivering thermogenesis. Shivering is a repetitive contraction-relaxation process activated by repeated stimulation of the neuromuscular junction that leads to elevation of cytosolic Ca++ concentration, thereby activating ATP hydrolysis to produce heat. During shivering, heat is primarily generated by the major ATP-utilizing enzymes, including Na+/K+ ATPase, myosin ATPase, and sarcoplasmic/endoplasmic reticulum Ca++ transport ATPase (SERCA) [102, 103]. In a cold environment, heat production increases by 10–30 W during the initial first minutes without any increase of muscle activity [104]. Later, extra heat is generated by involuntary contractions of skeletal muscles (shivering). Heat production through muscle shivering is well known as the first line of defense to acute cold exposure. Acute exposure to cold triggers immediate responses with the dual purpose of minimizing heat loss and producing heat. Shivering occurs when the core and skin temperature surpass a certain threshold and may produce heat equivalent to about four times resting metabolism. There are vasoconstriction and furred mammals undergo piloerection.

Heat production is initiated instantly by shivering, the direct form of facultative thermogenesis. Muscle contraction increases heat production. However, facultative shivering thermogenesis is a very high energy cost and disrupts activity [105]. Also, it is hence of limited value and rapidly replaced by non-shivering facultative thermogenesis [106]. The facultative thermogenesis resides in another evolutionary homeostatic advancement to adapt to the cold, the BAT (Figure 3).

Figure 3: Cold adaptation: energy dissipation, non-shivering thermogenesis.Heat production is initiated instantly by shivering, the direct form of facultative thermogenesis. Muscle contraction increases heat production. Skeletal muscle could serve as a site of non-shivering besides BAT in mammals, including humans. During cold acclimation, shivering is gradually replaced by non-shivering thermogenesis because repetitive muscle contractions during constant shivering can cause muscle damage.
Figure 3:

Cold adaptation: energy dissipation, non-shivering thermogenesis.

Heat production is initiated instantly by shivering, the direct form of facultative thermogenesis. Muscle contraction increases heat production. Skeletal muscle could serve as a site of non-shivering besides BAT in mammals, including humans. During cold acclimation, shivering is gradually replaced by non-shivering thermogenesis because repetitive muscle contractions during constant shivering can cause muscle damage.

People who have adapted to cold environments show some resistance to the development of diabetes, possibly due to the maintenance of larger amounts of BAT [107]. Likewise, the extent of human BAT activity in patients is inversely associated with obesity, age and type II diabetes [108]. In a comparison of overweight and lean subjects on thermogenesis in response to mild cold, the increase in heat production in response to a mild cold stimulus was observed to be three times as large in lean subjects compared with overweight subjects [104]. The mouse strains with higher thermogenic gene expression in WAT depots tended to be more resistant to obesity and insulin resistance than those with lower levels [109].

We know now that skeletal muscle could serve as a place of non-shivering besides BAT in mammals, including humans. During cold acclimation, shivering is gradually replaced by NST to save muscle and prevent muscle injury due to repetitive contractions during constant shivering [110]. Moreover, high-intensity shivering relies predominantly on muscle glycogen that can become limiting after a few hours [111].

The question is whether muscle will become a major site of NST when the BAT function is minimized in mice. The interscapular BAT (iBAT, which constitutes approximately 70% of total BAT) has been surgically removed, and mice exposed to prolonged cold (4° C) for nine days. Interestingly, the iBAT-ablated mice have maintained optimal body temperature (approximately 35–37° C) during the entire period of cold exposure. After four days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body mass and fat mass, showing a raised energy cost of cold adaptation. Moreover, the skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of the main components of Ca++ handling and mitochondrial metabolism. The changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. Therefore, the skeletal muscle becomes the major site of NST when BAT activity is minimized [112]. The heat production in skeletal muscle is tightly associated with sarcolipin, a regulator of SERCA [113].

Expert opinion

The recent discovery that adult humans possess adipocytes capable of performing thermogenesis opened the possibility to target new strategies to fight obesity and its comorbidities. Even though many studies have arisen, showing promising results and bringing new opportunities, the understanding of the browning phenomenon and its metabolic effects configures a new field of study, with many questions to be answered.


Browning is regarded as a new potential strategy to fight obesity. The experimental background provides a large body of evidence for body mass control, improved glucose handling and beneficial metabolic outcomes after the induction of brite adipocytes formation by nutritional or pharmacological approaches. The main challenge in the upcoming years will be to determine the actual impact of the brite adipocyte on human obesity as the translational potential of the experimental evidence remains to be unraveled.


  • Browning is characterized by the brown-like phenotype acquisition by white adipocytes, mainly from subcutaneous depots;

  • The identification of brite adipocytes in humans challenged the understanding of the metabolic pathways involved in the browning;

  • Adrenergic stimulation is crucial to trigger browning as it initiates the thermogenic pathway;

  • PGC1-α is a key factor to drive browning as it stimulates mitochondrial biogenesis and UCP1 transcription;

  • PPAR-α activation is linked to irisin induction and enhanced UCP1 transcription and activity;

  • In the recent years, many nutritional compounds have been studied as promoters of browning in white adipose tissue;

  • Capsaicin, bile acids, Resveratrol, retinoic acid and some classes of lipids are among the most studied nutrients that induce browning;

  • The potential of brite adipocytes to counter obesity in humans remains to be unraveled.


The authors disclose any conflict of interest in the present review. The Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases ( is currently sponsored by the following grants: a) Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ), grant numbers 202.126/2015 to TCLB, 202.888/2015 to VSM, 201.335/2014 to MBA, and 201.186/2014 to CAML. b) Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), grant numbers 306.077/2013-2 to MBA, and 302.154/2011-6 to CAML.

  1. Author Statement

  2. Funding: Authors state no funding involved.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Material and methods: Informed consent: Informed consent is not applicable.

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


1. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150:366–76.10.1016/j.cell.2012.05.016Search in Google Scholar PubMed PubMed Central

2. Lee P, Werner CD, Kebebew E, Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes (Lond) 2014;38:170–6.10.1038/ijo.2013.82Search in Google Scholar PubMed PubMed Central

3. Barquissau V, Beuzelin D, Pisani DF, Beranger GE, Mairal A, Montagner A, Roussel B, Tavernier G, Marques MA, Moro C, Guillou H, Amri EZ, Langin D. White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways. Mol Metab 2016;5:352–65.10.1016/j.molmet.2016.03.002Search in Google Scholar PubMed PubMed Central

4. Gustafson B, Smith U. Regulation of white adipogenesis and its relation to ectopic fat accumulation and cardiovascular risk. Atherosclerosis 2015;241:27–35.10.1016/j.atherosclerosis.2015.04.812Search in Google Scholar PubMed

5. Spiegelman BM. Banting Lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes 2013;62:1774–82.10.2337/db12-1665Search in Google Scholar PubMed PubMed Central

6. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013;27:234–50.10.1101/gad.211649.112Search in Google Scholar PubMed PubMed Central

7. Warner A, Mittag J. Breaking BAT: can browning create a better white? J Endocrinol 2016;228:R19–29.10.1530/JOE-15-0408Search in Google Scholar PubMed

8. Betz MJ, Enerback S. Human brown adipose tissue: what we have learned so far. Diabetes 2015;64:2352–60.10.2337/db15-0146Search in Google Scholar PubMed

9. Bargut TC, Aguila MB, Mandarim-de-Lacerda CA. Brown adipose tissue: Updates in cellular and molecular biology. Tissue Cell 2016;48:452–60.10.1016/j.tice.2016.08.001Search in Google Scholar PubMed

10. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K, Nedergaard J, Cannon B. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci U S A 2007;104:4401–6.10.1073/pnas.0610615104Search in Google Scholar PubMed PubMed Central

11. Park A, Kim WK, Bae KH. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J Stem Cells 2014;6:33–42.10.4252/wjsc.v6.i1.33Search in Google Scholar PubMed PubMed Central

12. Baboota RK, Sarma SM, Boparai RK, Kondepudi KK, Mantri S, Bishnoi M. Microarray based gene expression analysis of murine brown and subcutaneous adipose tissue: significance with human. PLoS One 2015;10:e0127701.10.1371/journal.pone.0127701Search in Google Scholar PubMed PubMed Central

13. Booth A, Magnuson A, Fouts J, Foster MT. Adipose tissue: an endocrine organ playing a role in metabolic regulation. Horm Mol Biol Clin Investig 2016;26:25–42.10.1515/hmbci-2015-0073Search in Google Scholar PubMed

14. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 2010;285:7153–64.10.1074/jbc.M109.053942Search in Google Scholar PubMed PubMed Central

15. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab 2015;21:33–8.10.1016/j.cmet.2014.12.009Search in Google Scholar PubMed PubMed Central

16. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526–31.10.2337/db09-0530Search in Google Scholar PubMed PubMed Central

17. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444–52.10.1152/ajpendo.00691.2006Search in Google Scholar PubMed

18. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012;7:e49452.10.1371/journal.pone.0049452Search in Google Scholar PubMed PubMed Central

19. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–17.10.1056/NEJMoa0810780Search in Google Scholar PubMed PubMed Central

20. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518–25.10.1056/NEJMoa0808949Search in Google Scholar PubMed

21. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013;19:635–9.10.1038/nm.3112Search in Google Scholar PubMed PubMed Central

22. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 2013;5:1196–203.10.1016/j.celrep.2013.10.044Search in Google Scholar PubMed

23. Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, Lo JC, Zeng X, Ye L, Khandekar MJ, Wu J, Gunawardana SC, Banks AS, Camporez JP, Jurczak MJ, Kajimura S, Piston DW, Mathis D, Cinti S, Shulman GI, Seale P, Spiegelman BM. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 2014;156:304–16.10.1016/j.cell.2013.12.021Search in Google Scholar PubMed PubMed Central

24. Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, Kurokawa M, Won KJ, Seale P. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab 2014;19:593–604.10.1016/j.cmet.2014.03.007Search in Google Scholar PubMed PubMed Central

25. Mirbolooki MR, Upadhyay SK, Constantinescu CC, Pan ML, Mukherjee J. Adrenergic pathway activation enhances brown adipose tissue metabolism: a [(1)(8)F]FDG PET/CT study in mice. Nucl Med Biol 2014;41:10–6.10.1016/j.nucmedbio.2013.08.009Search in Google Scholar PubMed PubMed Central

26. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009;23:3113–20.10.1096/fj.09-133546Search in Google Scholar PubMed

27. Bartness TJ, Liu Y, Shrestha YB, Ryu V. Neural innervation of white adipose tissue and the control of lipolysis. Front Neuroendocrinol 2014;35:473–93.10.1016/j.yfrne.2014.04.001Search in Google Scholar PubMed PubMed Central

28. Robidoux J, Cao W, Quan H, Daniel KW, Moukdar F, Bai X, Floering LM, Collins S. Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol 2005;25:5466–79.10.1128/MCB.25.13.5466-5479.2005Search in Google Scholar PubMed PubMed Central

29. Hondares E, Rosell M, Diaz-Delfin J, Olmos Y, Monsalve M, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha (PPARalpha) induces PPARgamma coactivator 1alpha (PGC-1alpha) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16. J Biol Chem 2011;286:43112–22.10.1074/jbc.M111.252775Search in Google Scholar PubMed PubMed Central

30. Piantadosi CA, Suliman HB. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem 2006;281:324–33.10.1074/jbc.M508805200Search in Google Scholar PubMed

31. Jeremic N, Chaturvedi P, Tyagi SC. Browning of white fat: novel insight into factors, mechanisms, and therapeutics. J Cell Physiol 2017;232:61–8.10.1002/jcp.25450Search in Google Scholar

32. Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, Vencato J, De Stefani D, Silvestrin V, Rizzuto R, Bassetto F, De Caro R, Vettor R. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol 2014;383:137–46.10.1016/j.mce.2013.12.005Search in Google Scholar

33. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003;113:159–70.10.1016/S0092-8674(03)00269-1Search in Google Scholar

34. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem 2001;276:1486–93.10.1074/jbc.M006246200Search in Google Scholar PubMed

35. Villarroya F, Iglesias R, Giralt M. PPARs in the control of uncoupling proteins gene expression. PPAR Res 2007;2007:74364.10.1155/2007/74364Search in Google Scholar PubMed PubMed Central

36. Serviddio G, Giudetti AM, Bellanti F, Priore P, Rollo T, Tamborra R, Siculella L, Vendemiale G, Altomare E, Gnoni GV. Oxidation of hepatic carnitine palmitoyl transferase-I (CPT-I) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet. PLoS One 2011;6:e24084.10.1371/journal.pone.0024084Search in Google Scholar PubMed PubMed Central

37. Sanchez-Gurmaches J, Guertin DA. Adipocyte lineages: tracing back the origins of fat. Biochim Biophys Acta 2014;1842:340–51.10.1016/j.bbadis.2013.05.027Search in Google Scholar PubMed PubMed Central

38. Long JZ, Svensson KJ, Tsai L, Zeng X, Roh HC, Kong X, Rao RR, Lou J, Lokurkar I, Baur W, Castellot JJ, Jr., Rosen ED, Spiegelman BM. A smooth muscle-like origin for beige adipocytes. Cell Metab 2014;19:810–20.10.1016/j.cmet.2014.03.025Search in Google Scholar PubMed PubMed Central

39. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463–8.10.1038/nature10777Search in Google Scholar PubMed PubMed Central

40. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Belen Crujeiras A, Seoane LM, Casanueva FF, Pardo M. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One 2013;8:e60563.10.1371/journal.pone.0060563Search in Google Scholar PubMed PubMed Central

41. Merlin J, Evans BA, Dehvari N, Sato M, Bengtsson T, Hutchinson DS. Could burning fat start with a brite spark? Pharmacological and nutritional ways to promote thermogenesis. Mol Nutr Food Res 2016;60:18–42.10.1002/mnfr.201500251Search in Google Scholar PubMed

42. Jimenez M, Barbatelli G, Allevi R, Cinti S, Seydoux J, Giacobino JP, Muzzin P, Preitner F. Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat. Eur J Biochem 2003;270:699–705.10.1046/j.1432-1033.2003.03422.xSearch in Google Scholar PubMed

43. Huang W, Bansode RR, Bal NC, Mehta M, Mehta KD. Protein kinase Cbeta deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling. J Lipid Res 2012;53:368–78.10.1194/jlr.M019687Search in Google Scholar PubMed PubMed Central

44. Li P, Zhu Z, Lu Y, Granneman JG. Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor-alpha. Am J Physiol Endocrinol Metab 2005;289:E617–26.10.1152/ajpendo.00010.2005Search in Google Scholar PubMed

45. Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. PPAR-alpha agonist elicits metabolically active brown adipocytes and weight loss in diet-induced obese mice. Cell Biochem Funct 2015;33:249–56.10.1002/cbf.3111Search in Google Scholar PubMed

46. Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Mol Cell Endocrinol 2015;402:86–94.10.1016/j.mce.2014.12.027Search in Google Scholar PubMed

47. Magliano DC, Bargut TC, de Carvalho SN, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Peroxisome proliferator-activated receptors-alpha and gamma are targets to treat offspring from maternal diet-induced obesity in mice. PLoS One 2013;8:e64258.10.1371/journal.pone.0064258Search in Google Scholar PubMed PubMed Central

48. Barbosa-da-Silva S, Souza-Mello V, Magliano DC, Marinho Tde S, Aguila MB, Mandarim-de-Lacerda CA. Singular effects of PPAR agonists on nonalcoholic fatty liver disease of diet-induced obese mice. Life Sci 2015;127:73–81.10.1016/j.lfs.2015.02.003Search in Google Scholar PubMed

49. Gaidhu MP, Fediuc S, Anthony NM, So M, Mirpourian M, Perry RL, Ceddia RB. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. J Lipid Res 2009;50:704–15.10.1194/jlr.M800480-JLR200Search in Google Scholar PubMed PubMed Central

50. Wu MV, Bikopoulos G, Hung S, Ceddia RB. Thermogenic capacity is antagonistically regulated in classical brown and white subcutaneous fat depots by high fat diet and endurance training in rats: impact on whole-body energy expenditure. J Biol Chem 2014;289:34129–40.10.1074/jbc.M114.591008Search in Google Scholar PubMed PubMed Central

51. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302–9.10.1016/j.cmet.2013.12.017Search in Google Scholar PubMed PubMed Central

52. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271–81.10.1101/gad.177857.111Search in Google Scholar PubMed PubMed Central

53. Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol Metab 2008;19:130–7.10.1016/j.tem.2007.11.006Search in Google Scholar PubMed

54. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012;122:1022–36.10.1172/JCI59701Search in Google Scholar PubMed PubMed Central

55. Zoli M, Picciotto MR. Nicotinic regulation of energy homeostasis. Nicotine Tob Res 2012;14:1270–90.10.1093/ntr/nts159Search in Google Scholar PubMed PubMed Central

56. Chen H, Vlahos R, Bozinovski S, Jones J, Anderson GP, Morris MJ. Effect of short-term cigarette smoke exposure on body weight, appetite and brain neuropeptide Y in mice. Neuropsychopharmacology 2005;30:713–9.10.1038/sj.npp.1300597Search in Google Scholar PubMed

57. Yoshida T, Sakane N, Umekawa T, Kogure A, Kondo M, Kumamoto K, Kawada T, Nagase I, Saito M. Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice. Int J Obes Relat Metab Disord 1999;23:570–5.10.1038/sj.ijo.0800870Search in Google Scholar PubMed

58. Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008;454:1000–4.10.1038/nature07221Search in Google Scholar PubMed PubMed Central

59. Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach JL, Cerletti M, McDougall LE, Giorgadze N, Tchkonia T, Schrier D, Falb D, Kirkland JL, Wagers AJ, Tseng YH. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci U S A 2011;108:143–8.10.1073/pnas.1010929108Search in Google Scholar PubMed PubMed Central

60. Elsen M, Raschke S, Tennagels N, Schwahn U, Jelenik T, Roden M, Romacho T, Eckel J. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells. Am J Physiol Cell Physiol 2014;306:C431–40.10.1152/ajpcell.00290.2013Search in Google Scholar PubMed

61. Richard D, Carpentier AC, Dore G, Ouellet V, Picard F. Determinants of brown adipocyte development and thermogenesis. Int J Obes (Lond) 2010;34:Suppl 2:S59–66.10.1038/ijo.2010.241Search in Google Scholar PubMed

62. Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, Lopez M, Vidal-Puig A. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012;149:871–85.10.1016/j.cell.2012.02.066Search in Google Scholar PubMed PubMed Central

63. Kieffer TJ, Habener JF. The adipoinsular axis: effects of leptin on pancreatic beta-cells. Am J Physiol Endocrinol Metab 2000;278:E1–14.10.1152/ajpendo.2000.278.1.E1Search in Google Scholar PubMed

64. Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Munzberg H, Zhang ZY, Kahn BB, Neel BG, Bence KK, Andrews ZB, Cowley MA, Tiganis T. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 2015;160:88–104.10.1016/j.cell.2014.12.022Search in Google Scholar PubMed PubMed Central

65. Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 2014;19:741–56.10.1016/j.cmet.2014.02.007Search in Google Scholar PubMed PubMed Central

66. Lee JY, Takahashi N, Yasubuchi M, Kim YI, Hashizaki H, Kim MJ, Sakamoto T, Goto T, Kawada T. Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Physiol Cell Physiol 2012;302:C463–72.10.1152/ajpcell.00010.2011Search in Google Scholar PubMed

67. Joo JI, Kim DH, Choi JW, Yun JW. Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. J Proteome Res 2010;9:2977–87.10.1021/pr901175wSearch in Google Scholar PubMed

68. Baboota RK, Singh DP, Sarma SM, Kaur J, Sandhir R, Boparai RK, Kondepudi KK, Bishnoi M. Capsaicin induces “brite” phenotype in differentiating 3T3-L1 preadipocytes. PLoS One 2014;9:e103093.10.1371/journal.pone.0103093Search in Google Scholar PubMed PubMed Central

69. Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol 2016;173:2369-89.10.1111/bph.13514Search in Google Scholar PubMed PubMed Central

70. Hasek BE, Stewart LK, Henagan TM, Boudreau A, Lenard NR, Black C, Shin J, Huypens P, Malloy VL, Plaisance EP, Krajcik RA, Orentreich N, Gettys TW. Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol 2010;299:R728–39.10.1152/ajpregu.00837.2009Search in Google Scholar PubMed PubMed Central

71. Jha P, Knopf A, Koefeler H, Mueller M, Lackner C, Hoefler G, Claudel T, Trauner M. Role of adipose tissue in methionine-choline-deficient model of non-alcoholic steatohepatitis. Biochim Biophys Acta 2014;1842:959–70.10.1016/j.bbadis.2014.02.012Search in Google Scholar PubMed PubMed Central

72. Plaisance EP, Henagan TM, Echlin H, Boudreau A, Hill KL, Lenard NR, Hasek BE, Orentreich N, Gettys TW. Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction. Am J Physiol Regul Integr Comp Physiol 2010;299:R740–50.10.1152/ajpregu.00838.2009Search in Google Scholar PubMed PubMed Central

73. Delahaye F, Lukaszewski MA, Wattez JS, Cisse O, Dutriez-Casteloot I, Fajardy I, Montel V, Dickes-Coopman A, Laborie C, Lesage J, Breton C, Vieau D. Maternal perinatal undernutrition programs a “brown-like” phenotype of gonadal white fat in male rat at weaning. Am J Physiol Regul Integr Comp Physiol 2010;299:R101–10.10.1152/ajpregu.00604.2009Search in Google Scholar PubMed

74. Maeda H, Hosokawa M, Sashima T, Funayama K, Miyashita K. Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. Biochem Biophys Res Commun 2005;332:392–7.10.1016/j.bbrc.2005.05.002Search in Google Scholar PubMed

75. Maeda H, Hosokawa M, Sashima T, Miyashita K. Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-Ay mice. J Agric Food Chem 2007;55:7701–6.10.1021/jf071569nSearch in Google Scholar PubMed

76. Maeda H, Hosokawa M, Sashima T, Murakami-Funayama K, Miyashita K. Anti-obesity and anti-diabetic effects of fucoxanthin on diet-induced obesity conditions in a murine model. Mol Med Rep 2009;2:897–902.10.3892/mmr_00000189Search in Google Scholar PubMed

77. Zhang X, Zhang QX, Wang X, Zhang L, Qu W, Bao B, Liu CA, Liu J. Dietary luteolin activates browning and thermogenesis in mice through an AMPK/PGC1alpha pathway-mediated mechanism. Int Int J Obes (Lond) 2016;40:1841–9.10.1038/ijo.2016.108Search in Google Scholar PubMed

78. Joffin N, Jaubert AM, Bamba J, Barouki R, Noirez P, Forest C. Acute induction of uncoupling protein 1 by citrulline in cultured explants of white adipose tissue from lean and high-fat-diet-fed rats. Adipocyte 2015;4:129–34.10.4161/21623945.2014.989748Search in Google Scholar PubMed PubMed Central

79. Teodoro JS, Zouhar P, Flachs P, Bardova K, Janovska P, Gomes AP, Duarte FV, Varela AT, Rolo AP, Palmeira CM, Kopecky J. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice. Int J Obes (Lond) 2014;38:1027–34.10.1038/ijo.2013.230Search in Google Scholar PubMed

80. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484–9.10.1038/nature04330Search in Google Scholar PubMed

81. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159–65.10.1038/nm.3760Search in Google Scholar

82. Mercader J, Palou A, Bonet ML. Resveratrol enhances fatty acid oxidation capacity and reduces resistin and Retinol-Binding Protein 4 expression in white adipocytes. J Nutr Biochem 2011;22:828–34.10.1016/j.jnutbio.2010.07.007Search in Google Scholar

83. Wang S, Liang X, Yang Q, Fu X, Rogers CJ, Zhu M, Rodgers BD, Jiang Q, Dodson MV, Du M. Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) alpha1. Int J Obes (Lond) 2015;39:967–76.10.1038/ijo.2015.23Search in Google Scholar

84. Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res 2008;22:1367–71.10.1002/ptr.2503Search in Google Scholar

85. Calder PC. Functional roles of fatty acids and their effects on human health. J Parenter Enteral Nutr 2015;39:18S–32S.10.1177/0148607115595980Search in Google Scholar

86. Zhao M, Chen X. Eicosapentaenoic acid promotes thermogenic and fatty acid storage capacity in mouse subcutaneous adipocytes. Biochem Biophys Res Commun 2014;450:1446–51.10.1016/j.bbrc.2014.07.010Search in Google Scholar

87. Bargut TC, Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB. Fish oil diet modulates epididymal and inguinal adipocyte metabolism in mice. Food Funct 2016;7:1468–76.10.1039/C5FO00909JSearch in Google Scholar

88. Wendel AA, Purushotham A, Liu LF, Belury MA. Conjugated linoleic acid induces uncoupling protein 1 in white adipose tissue of ob/ob mice. Lipids 2009;44:975–82.10.1007/s11745-009-3348-9Search in Google Scholar

89. Peters JM, Park Y, Gonzalez FJ, Pariza MW. Influence of conjugated linoleic acid on body composition and target gene expression in peroxisome proliferator-activated receptor alpha-null mice. Biochim Biophys Acta 2001;1533:233–42.10.1016/S1388-1981(01)00155-XSearch in Google Scholar

90. Vogler O, Lopez-Bellan A, Alemany R, Tofe S, Gonzalez M, Quevedo J, Pereg V, Barcelo F, Escriba PV. Structure-effect relation of C18 long-chain fatty acids in the reduction of body weight in rats. Int J Obes (Lond) 2008;32:464–73.10.1038/sj.ijo.0803768Search in Google Scholar PubMed

91. Murholm M, Isidor MS, Basse AL, Winther S, Sorensen C, Skovgaard-Petersen J, Nielsen MM, Hansen AS, Quistorff B, Hansen JB. Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. BMC Cell Biol 2013;14:41.10.1186/1471-2121-14-41Search in Google Scholar PubMed PubMed Central

92. Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol 2009;29:3286–96.10.1128/MCB.01742-08Search in Google Scholar PubMed PubMed Central

93. Mercader J, Ribot J, Murano I, Felipe F, Cinti S, Bonet ML, Palou A. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology 2006;147:5325–32.10.1210/en.2006-0760Search in Google Scholar PubMed

94. Mercader J, Palou A, Bonet ML. Induction of uncoupling protein-1 in mouse embryonic fibroblast-derived adipocytes by retinoic acid. Obesity (Silver Spring) 2010;18:655–62.10.1038/oby.2009.330Search in Google Scholar PubMed

95. Choi JH, Kim SW, Yu R, Yun JW. Monoterpene phenolic compound thymol promotes browning of 3T3-L1 adipocytes. Eur J Nutr 2016 (doi:10.1007/s00394-016-1273-2). In press.Search in Google Scholar PubMed

96. Choi WH, Ahn J, Jung CH, Jang YJ, Ha TY. Beta-lapachone prevents diet-induced obesity by increasing energy expenditure and stimulating the browning of white adipose tissue via down-regulation of miR-382 expression. Diabetes 2016 (doi: 10.2337/db15-1423).Search in Google Scholar PubMed

97. Kanamoto Y, Yamashita Y, Nanba F, Yoshida T, Tsuda T, Fukuda I, Nakamura-Tsuruta S, Ashida H. A black soybean seed coat extract prevents obesity and glucose intolerance by up-regulating uncoupling proteins and down-regulating inflammatory cytokines in high-fat diet-fed mice. J Agric Food Chem 2011;59:8985–93.10.1021/jf201471pSearch in Google Scholar PubMed

98. Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, Yao S, Ma Q, Jin L, Yang J, Wang W, Ning G. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014;5:5493.10.1038/ncomms6493Search in Google Scholar PubMed

99. Nishikawa S, Aoyama H, Kamiya M, Higuchi J, Kato A, Soga M, Kawai T, Yoshimura K, Kumazawa S, Tsuda T. Artepillin C, a Typical Brazilian Propolis-Derived Component, Induces Brown-Like Adipocyte Formation in C3H10T1/2 Cells, Primary Inguinal White Adipose Tissue-Derived Adipocytes, and Mice. PLoS One 2016;11:e0162512.10.1371/journal.pone.0162512Search in Google Scholar PubMed PubMed Central

100. Carriere A, Jeanson Y, Berger-Muller S, Andre M, Chenouard V, Arnaud E, Barreau C, Walther R, Galinier A, Wdziekonski B, Villageois P, Louche K, Collas P, Moro C, Dani C, Villarroya F, Casteilla L. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes 2014;63:3253–65.10.2337/db13-1885Search in Google Scholar PubMed

101. Roberts LD, Ashmore T, Kotwica AO, Murfitt SA, Fernandez BO, Feelisch M, Murray AJ, Griffin JL. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 2015;64:471–84.10.2337/db14-0496Search in Google Scholar PubMed PubMed Central

102. Haman F. Shivering in the cold: from mechanisms of fuel selection to survival. J Appl Physiol 2006;100:1702–8.10.1152/japplphysiol.01088.2005Search in Google Scholar PubMed

103. Rowland LA, Bal NC, Periasamy M. The role of skeletal-muscle-based thermogenic mechanisms in vertebrate endothermy. Biol Rev Camb Philos Soc 2015;90:1279–97.10.1111/brv.12157Search in Google Scholar PubMed PubMed Central

104. Claessens-van Ooijen AM, Westerterp KR, Wouters L, Schoffelen PF, van Steenhoven AA, van Marken Lichtenbelt WD. Heat production and body temperature during cooling and rewarming in overweight and lean men. Obesity (Silver Spring) 2006;14:1914–20.10.1038/oby.2006.223Search in Google Scholar PubMed

105. Haman F, Peronnet F, Kenny GP, Massicotte D, Lavoie C, Scott C, Weber JM. Effect of cold exposure on fuel utilization in humans: plasma glucose, muscle glycogen, and lipids. J Appl Physiol 2002;93:77–84.10.1152/japplphysiol.00773.2001Search in Google Scholar PubMed

106. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277–359.10.1152/physrev.00015.2003Search in Google Scholar PubMed

107. Dayaratne DA. Impact of ecology on development of NIDDM. Med Hypotheses 2010;74:986–8.10.1016/j.mehy.2009.12.017Search in Google Scholar PubMed

108. Lee P, Swarbrick MM, Ho KK. Brown adipose tissue in adult humans: a metabolic renaissance. Endocr Rev 2013;34:413–38.10.1210/er.2012-1081Search in Google Scholar PubMed

109. Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 1998;102:412–20.10.1172/JCI3155Search in Google Scholar PubMed PubMed Central

110. Aydin J, Shabalina IG, Place N, Reiken S, Zhang SJ, Bellinger AM, Nedergaard J, Cannon B, Marks AR, Bruton JD, Westerblad H. Nonshivering thermogenesis protects against defective calcium handling in muscle. FASEB J 2008;22:3919–24.10.1096/fj.08-113712Search in Google Scholar PubMed PubMed Central

111. Haman F, Mantha OL, Cheung SS, DuCharme MB, Taber M, Blondin DP, McGarr GW, Hartley GL, Hynes Z, Basset FA. Oxidative fuel selection and shivering thermogenesis during a 12- and 24-h cold-survival simulation. J Appl Physiol (1985) 2016;120:640–8.10.1152/japplphysiol.00540.2015Search in Google Scholar PubMed

112. Bal NC, Maurya SK, Singh S, Wehrens XH, Periasamy M. increased reliance on muscle-based thermogenesis upon acute minimization of brown adipose tissue function. J Biol Chem 2016;291:17247–57.10.1074/jbc.M116.728188Search in Google Scholar PubMed PubMed Central

113. Bal NC, Maurya SK, Sopariwala DH, Sahoo SK, Gupta SC, Shaikh SA, Pant M, Rowland LA, Bombardier E, Goonasekera SA, Tupling AR, Molkentin JD, Periasamy M. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 2012;18:1575–9.10.1038/nm.2897Search in Google Scholar PubMed PubMed Central

Received: 2016-11-8
Accepted: 2016-12-1
Published Online: 2017-1-18

©2017 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 29.9.2023 from
Scroll to top button