What this is
- Adipose tissue is categorized into white, brown, and beige types, each with distinct functions.
- , which can be recruited from white fat, plays a role in energy metabolism and type 2 diabetes.
- This review explores agents that promote the of white fat and their implications for metabolic health.
Essence
- of white adipose tissue can enhance energy metabolism and may help combat type 2 diabetes. Various agents, including dietary compounds and physiological stimuli, have been identified to promote this process.
Key takeaways
- Beige adipocytes can be recruited from white adipose tissue, contributing to thermogenesis and energy expenditure. This recruitment is significant for improving glucose homeostasis and insulin sensitivity.
- Physiological stimuli such as cold exposure and dietary factors like capsaicin and resveratrol have been shown to induce of white fat. These agents work through various mechanisms, including modulation of key transcription factors.
- The review emphasizes the potential of targeting and agents in developing treatments for obesity and type 2 diabetes, highlighting non-invasive strategies with fewer side effects.
Caveats
- The review primarily discusses findings from animal models, which may not fully translate to human physiology. Further research is needed to confirm these effects in human populations.
- Many agents are still under investigation, and their long-term safety and efficacy in humans remain unclear.
Definitions
- Beige adipose tissue: A type of fat that shares characteristics with brown fat but is derived from white fat precursors and can be recruited in adults.
- Browning: The process by which white adipose tissue acquires characteristics of brown fat, including increased thermogenic capacity.
AI simplified
Introduction
Traditionally, adipose tissues have been divided into subcategories of white adipose tissue (WAT) and brown adipose tissue (BAT) according to their function and morphology. BAT functions in thermogenesis generating heat through combustion of nutrients that is uncoupled from ATP production by uncoupling protein (UCP1). Besides, the main functions of energy storage (WAT) and heat production (BAT) are considered endocrine tissues due to secretion of adipokines that participate in metabolic regulation of the body [14]. Newest addition, beige adipose tissue, has been established as an intermediate between BAT and WAT. The tissue shares the ability to thermogenesis as well as morphological features. Beige fat tissue derives from precursors of white adipocytes [27, 45] and is found in clusters scattered within the areas of white adipose tissue as opposed to occurrence of BAT in separate and distinct depots.
An aspect of interest in beige adipose tissue is that beige adipocytes have been demonstrated to be recruitable. Beige adipocytes exhibit low basal expression level of UCP1 and other thermogenesis related genes that are inducible upon stimulus, such as cold stimulation [26, 84, 91]. Theories behind the origin of beige adipocytes include (i) trans-differentiation from mature white adipocytes, (ii) existence of a distinct beige fat cell precursor, and (iii) differentiation from brown or white adipocyte precursors [17, 60, 61]. It was previously suggested that browning is a feature of WAT instead of beige adipocytes being a distinct cell type, but this theory was heavily questioned by the findings on beige adipocyte gene expression pattern by Wu et al. [88].
Brown and beige adipocytes have raised an interest in health sciences with their capability to counteract different metabolic diseases, including obesity and type 2 diabetes. Thermogenesis without ATP production, orchestrated by UCP1, is an effective way of assisting energy wastage, thus creating a negative energy balance. While some metabolic disorders and obesity are commonly linked to type 2 diabetes, brown adipose tissue contributes directly to the disease onset and permanence. Obesity resistance has also been linked to activation of these tissues in several mouse models [9, 34, 66]. In addition, brown adipose tissue might exert a beneficial effect on whole-body metabolism via other routes, such as lipid and glucose clearance from circulation. Taking into account the beneficial effects of BAT occurrence, the emergence of thermogenesis-able beige adipocytes and browning of WAT hold an interest and potential towards treating type 2 diabetes. In addition, beige adipocytes are hypothesized to have a distinct role in metabolic regulation and exhibit different physiological purposes compared to classical brown adipocytes [45]. This review discusses different browning agents that have been discovered and studied so far in the context of diabetes type 2 treatment and/or effect of browning to glucose metabolism and insulin sensitivity.
Development of adipose tissues on the molecular level
Brown and white fat develop from mesoderm through separate differentiating lineages. Mesenchymal stem cells (MSCs; multipotent stem cells of the adipose tissue extracellular matrix) can commit to either adipogenic or myogenic lineage, leading to emergence of either white adipocytes, brown adipocytes, or myocytes. Classical brown adipocytes and myocytes develop along myogenic lineage and derive from myogenic factor 5 positive cells (Myof5+), whereas precursors of white and beige adipocytes are Myof5− and thus adipogenic [60, 67]. Despite sharing a precursor, beige fat cells exhibit distinct gene expression compared to either WAT or BAT, combining expression pattern of genes characteristic to WAT (adiponectin, adipocyte protein 2 gene (aP2), adipsin) and BAT (Ucp1, Cidea, Pgc-1α). In addition, beige fat cells express genes specific to the fat tissue, such as a developmental transcription factor T-box1 (Tbx1), a fatty acid transporter solute carrier family 27 member 1 (Slc27a1), and transmembrane protein 26 (TMEM26) as well as molecules of immune and inflammatory response pathways, such as CD40 and CD137 [88]. Distinct genetic loci drive the regulation of BAT and beige adipocytes, suggesting that different pathways are responsible for regulation of these tissues.
The differentiation processes of adipogenic and myogenic lineages are orchestrated with surprisingly similar transcriptional cascades. Peroxisome proliferator-activated receptor-γ (PPARγ) is the key switch determining the cell fate and differentiation to either a brown or a white adipocyte [29]. PPARγ drives the adipogenesis transcriptional program in co-operation with a set of different co-activators and regulators, such as CCAAT/enhancer binding proteins (C/EBS), PPARγ co-activator-1α (PGC-1α) and PRDM16. PGC-1α is the major regulator of mitochondrial biogenesis and oxidative metabolism in brown fat and other cell types, such as skeletal muscle, and one of the most important factors of brown adipocyte development [62]. PRDM16, a transcriptional co-regulator, is one of the key switches between determining the development into a brown adipocyte or a myocyte. PRDM16 functions by interacting with multiple DNA-binding transcriptional factors, such as PPARα, PPARγ, and several C/EBP protein family members and has the capability of inducing PGC-1α expression, while C/EBS participate in the upkeep of the differentiation state [29, 67]. In addition to major transcriptional switches PPARγ and PRDM16 that determine the cell fate between myocyte, WAT, and BAT, other overlapping cascades and molecular factors are also involved in adipogenesis and adipocyte differentiation.
BAT and beige connections to type 2 diabetes
BAT intakes glucose and lipids from circulation aiding in glucose clearance and relieving the demand for insulin secretion by β-cells, thus improving their function [45]. Fasting glucose concentrations in individuals with detectable BAT were demonstrated to be lower than in those without active BAT [38]. The predominant source of energy for brown adipose tissue metabolism is fatty acids stored in brown adipocytes [46], while only 10% of the energy is derived from plasma glucose. However, the clearance of this glucose has been demonstrated to be effective in diabetics. In humans, boosting of glucose uptake into BAT consists of two different mechanisms: insulin-dependent and insulin-independent [57]. Heat production-related glucose uptake into BAT has been suggested to be independent from insulin signaling, thus bypassing all the normal parameters regulating the blood glucose level [15, 50, 56]. BAT is one of the most sensitive target tissues for insulin action and is considered to be the most important metabolically active organ for glucose. BAT activation enhances insulin signaling in BAT itself by combining the insulin-independent glucose uptake with thermogenesis and uptake of the glucose administered by insulin signaling [45].
Many of the effects responsible for glucose and lipid clearance from plasma are indirectly improving the state of insulin resistance and β-cell failure. While glucolipotoxicity is one of the major pathologies behind insulin resistance, peripheral lipid and glucose clearance benefits β-cells and aids in restoring peripheral insulin sensitivity [59]. In practice, BAT-related treatment methods include (i) increasing the BAT mass, (ii) recruitment of beige adipocytes by browning of WAT, and (iii) boosting the effects of activation of already existing BAT by targeting the regulation of fuel uptake and utilization [57]. Formation of beige adipocytes has been demonstrated to have ameliorating effects to body weight as well as to glucose and lipid homeostasis [7, 50]. Physiological stimuli traditionally considered to induce the formation of beige adipocytes include cold exposure, diet, and exercise. In addition to activation of classical BAT, prolonged cold exposure, as well as β-adrenergic agonist treatment, has been demonstrated to be able to brown WAT [24, 25, 91].
Browning agents
| Factor | Publication | Key findings |
|---|---|---|
| Cold exposure | Young et al. 1984 | Cold induction leads to the emergence ofpositive cells and morphological changes in mouse parametrial fat badUcp1 |
| Cousin et al. 1992 | Cold exposure increases UCP1 expression in rodent periovarian WAT | |
| Wang and Wahl 2014 | Cold exposure stimulates BAT insulin signaling in rats | |
| CL 316243 | Ghorbani et al. 1997 | Chronic treatment with CL 316243 leads to occurrence of brown adipocytes within traditional WAT depots |
| BRL 26830A | Cousin et al. 1992 | Treatment with BRL 26830A increases UCP1 expression in periovarian WAT depots in rodents |
| Acetate | Sahuri-Arisoylu et al. 2016 | Acetate treatment show WAT browning capacity in mice |
| Capsaicin | Baskaran et al. 2016 | Capsaicin initiates WAT browning in mice by several different mechanisms |
| Resveratrol | Azhan et al. 2016 | Resveratrol induces Ucp1 and Pgc1α gene expression in mice |
| Berberine | Zhang et al. 2014 | Berberine induces development of brown-like adipocytes in inguinal WAT depot in mice |
| Fish oil | Kim et al. 2015 | Fish oil intake lead to upregulation of UCP1 and the β3 adrenergic receptor in inguinal WAT of mice |
| Decaffeinated green tea extract | Chen et al. 2017 | Decaffeinated green tea extract induces expression of variety of browning related biomarkers |
| Cinnamon | Kwan et al. 2017 | Cinnamon effects UCP1 expression in adipocytes isolated from mouse subcutaneous WAT |
| Ginsenodise Rb1CurcuminQuercetin | Mu et al. 2015Lone et al. 2016Lee et al. 2017 | Ginsenoside Rb1, curcumin and quercetin promote mRNA expression of BAT markers in 3T3-L1 cells |
| Farnesoid X receptor | Fang et al. 2014 | Farnesoid X receptor activation enhance thermogenesis and browning of subcutaneous WAT |
| Liver X receptors | Miao et al. 2015 | Liver X receptors regulate the browning of WAT, activation of mitochondria, and increased energy expenditure |
| MicroRNAs | Shamsi et al. 2017 | MicroRNAs regulate both BAT activation and subcutaneous WAT browning in cold exposure |
| Ng et al. 2017 | miRNA-32 has a role in cold-induced WAT browning | |
| Thiazolidinediones | Petrovic et al. 2010 | Chronic treatment with thiazolidinediones (TZDs) induces browning of WAT by activating PPARγ and PRDM16 |
| Prostaglandin E2 | Garcia-Alonso et al. 2014 | Prostaglandin E2 diverts preadipocyte differentiation in WAT to beige adipocytes |
| Gleevec | Choi et al. 2016 | Gleevec increases brown/beige fat thermogenic and mitochondrial genes in WAT and interscapular BAT in mice |
| Beta-lapachone | Choi et al. 2016 | Beta-lapachone stimulates browning of WAT and increases expression of UCP1 in high-fat diet fed mice |
| Slit 2 derived secretory product | Svensson et al. 2016 | Slit 2 derived secretory product regulates beige adipocyte induction via Prdm16 and activation of PKA signaling |
| Artepillin C | Nishikawa et al. 2016 | Artepillin C induces brown-like adipocytes in mice and primary inguinal WAT derived adipocytes in vitro |
| Adrenomedullin 2 | Zhang et al. 2016 | Adrenomedullin 2 induces browning of rat primary adipocytes in vitro |
| IL-6 | Abdullahi et al. 2017 | Il-6 originated from bone marrow in burn injury regulates WAT browning |
| IL-4 | Nguyen et al. 2011 | IL-4 exerts a macrophage-dependent role in BAT activation during cold exposure |
| IEX-1 | Shahid et al. 2016 | Deficiency of IEX-1 lead to WAT browning via alternative activation of macrophages |
| Thyroid hormones | Medina-Gomez et al. 2008 | Thyroid hormone metabolite TRIAC induces UCP1 expression in abdominal WAT of rats |
| Lee et al. 2012 | Treatment of human adipose-derived stem cells with T3 induces UCP1 expression and mitochondrial biogenesis | |
| Kir et al. 2014Thomas and Mitch 2017 | Parathyroid hormone (PTHr) and tumor-derived parathyroid hormone-related protein (PTHrP) administration leads to WAT browning in mice cancer-cachexia models | |
| Weiner et al. 2017 | Thyroid hormones induce WAT browning through both peripheral and central mechanisms | |
| Glucagon-like peptide 1 | Beiroa et al. 2014Lopez et al. 2015 | GLP1 stimulates WAT browning and stimulates BAT thermogenesis in mice |
| Leptin | Dodd et al. 2015 | Leptin drives WAT browning through action on hypothalamic neurons |
| Melatonin | Jiménez-Aranda et al. 2013 | Melatonin induces WAT browning on inguinal WAT in rats |
| Natriuretic peptides | Bordicchia et al. 2012Liu et al. 2018 | Natriuretic peptides demonstrate WAT browning capacity with several different mechanisms |
| PTENCox2Foxc2FolliculinGq | Klepac et al. 2016 | Distinct gene set is associated with WAT browning, including PTEN, Cox2, Foxc2, Folliculin, and Gq |
| TGF-β/Smad3 | Yaday and Rane 2012 | Modulations in TGF-β/Smad3 signaling activate BAT-like phenotype in rodent WAT |
| FGF21 | Fisher et al. 2012 | FGF21 expression is essential for cold-induced recruitment of beige adipocytes |
| Keipert and Jastroch 2014 | FGF21 secretion from skeletal muscle leads to increased browning of epididymal and subcutaneous fat depots in mice | |
| Apelin | Than et al. 2015 | Apelin secreted from brown and white adipocytes stimulates adipose browning |
| Exercise | Wu et al. 1999Villena et al. 2002 | Exercise induces expression of PGC-1α |
| Boström et al. 2012Lee et al. 2014 | Irisin released from muscle during exercise induces WAT browning in human and rodents | |
| PPAR agonists | Fukui et al. 2000Laplante et al. 2003 | Treatment with PPAR agonists increases UCP1 expression in different WAT depots |
| Ohno et al. 2012 | Browning effect of PPAR ligands is centered to stabilization and expression of PRDM16 | |
| Petrovic et al. 2010 | Rosiglitazone treatment induces browning of epididymal WAT depot in mice | |
| Zhao et al. 2016 | α/β-Hydrolase domain 6 negatively regulates adipose tissue browning | |
| BMPs | Tseng et al. 2008Shen et al. 2009 | BMP7 is able to induce BAT selective genes in preadipocytes and drive browning of mesenchymal progenitor cells |
| Elsen et al. 2014 | BMP7 and BMP4 induce white-to-brown shifting in primary human adipose stem cells | |
| Ross et al. 2000 | Wingless pathway (Wnt) activation represses brown and white adipogenesis by suppressing the induction of PPARγ and C/EBSα | |
| Lactateβ-hydroxybutyrate | Carrière et al. 2014 | Lactate and β-hydroxybutyrate increase UCP1 gene expression in human and murine WAT |
| Beta-aminoisobutyric acid (BAIBA) | Roberts et al. 2014 | BAIBA increases BAT marker genes in WAT of mice both in vitro and in vivo and BAT-like phenotype in human pluripotent stem cells |
| Retinoic acid | Wang et al. 2017 | Retinoic acid induces WAT browning through activation of vascular endothelial growth factor (VEGF) signaling in vitro |
Cold exposure
Cold exposure is one of the oldest and most studied physiological stimuli leading to WAT browning. In early studies in rodents, both acute and chronic cold exposure has been reported to increase oxygen consumption, stimulate BAT insulin signaling, and to lead to the emergence of Ucp1-positive cells and morphological changes in mouse parametrial fat bad [26, 84, 91]. Cousin et al. (1992) demonstrated increase in UCP1 expression in rodent periovarian WAT in response to prolonged cold exposure in + 4 °C [13]. Cold exposure induced browning in mice has also been studied by Vitali et al. (2012) and they suggest that the density of sympathetic nerves innervating WAT is one of the key features for the browning effect to take place [81]. However, very little is known about SNS innervation in WAT browning and beige adipocytes, underlining it as one important future research line [21].
β-3 adrenergic receptor agonists
In early rodent models of Ghorbani et al. (1997), chronic treatment with beta3-adrenoceptor agonist CL 316243 was shown to lead to occurrence of brown adipocytes within traditional WAT depots including mesenteric, inguinal, epididymal, and retroperitoneal fat depots [24]. Cousin et al. (1992) reported increase in UCP1 expression in periovarian WAT depots in rodents as a result for treatment with BRL 26830A [13].
Short-chain fatty acids
These are end products of microbial fermentation of carbohydrates and starch by colon and have been linked to changes in body weight, appetite, and adiposity. Namely, acetate, butyrate, and propionate have been the compounds of interest while demonstrating to have protective effect against diet-induced obesity and insulin resistance in mice models [41]. Acetate has been demonstrated with WAT browning capacity in mice model [65].
Dietary factors and organic compounds
Several plant-based compounds and dietary factors have been demonstrated to have browning effects based on studies done on mice or in vitro [85]. Capsaicin (and related capsinoids) has been demonstrated to initiate WAT browning in mice by several different mechanisms, including modulation of expression of PPARγ 1 co-activator α, facilitation of PPARγ–Prdm16 interaction, and promotion of sirtuin-1 (SirT1) expression [4]. Plant-produced resveratrol has been demonstrated to induce Ucp1 and Pgc1α gene expression, having similar effects to butein in a mice model [2]. Plant-derived berberine (BBR) has been shown to induce development of brown-like adipocytes in inguinal, but not epididymal adipose depots in mice through PGC-1α signaling [94]. Fish oil intake has been shown to lead to upregulation of UCP1 and the β3 adrenergic receptor in both interscapular BAT and inguinal WAT of mice [31]. In the study of Chen et al. (2017), decaffeinated green tea extract supplemented for mice induced expression of variety of browning-related biomarkers, including PPARγ, PRDM-16, BMP-7, FGF-21, UCP-1, CPT-1 CIDEA, and PGC-1α [10].
In cell culture models, cinnamon extract has been demonstrated to increase expression of brown adipocyte markers, decrease those of WAT, and induce BAT phenotype in cell culture models done with 3T3-L1 adipocyte cell line. In addition, cinnamon effected UCP1 expression in adipocytes isolated from mouse subcutaneous WAT [35]. Similarly to cinnamon, several other compounds have been studied to promote browning of 3T3-L1 cells as observed by significant increases in mRNA expressions of UCP-1, PGC-1α, and PRDM16, including ginsenoside Rb1, curcumin, and quercetin [40, 43, 51].
Nuclear receptors and ligands
Bile acid-activated nuclear receptor, farnesoid X receptor (FXR) regulates bile acid, lipid and glucose homeostasis, and several other regulatory functions in the intestinal tract. FXR activation with fexaramine antagonist has been demonstrated to enhance thermogenesis and browning of subcutaneous WAT [19]. Liver X receptors (LXRs), nuclear receptors that control lipid and glucose metabolism, have been reported to be able to regulate the browning of WAT, activation of mitochondria, and increased energy expenditure [49].
MicroRNAs
Different microRNA types and their roles have been studied also in terms of WAT browning and adipose tissue physiology. MicroRNAs have been shown to regulate both BAT activation and subcutaneous WAT browning in cold exposure [70]. miRNA-32 inhibition in vivo has been demonstrated to reduce FGF21 expression and compromise tolerance to cold, thus having a role in cold-induced WAT browning [52]. MiRNA-455 has been studied to enhance WAT browning response to cold and norepinephrine stimulation [92]. In contrast, several miRNA types act as negative regulators of WAT browning and BAT activity [70].
Drug agents
Chronic treatment with thiazolidinediones (TZDs) has been demonstrated to induce browning of WAT by activating PPARγ and PRDM16 [60]. Prostaglandin E2 (PGE2) is a PPARγ co-operator that has been demonstrated to divert preadipocyte differentiation in WAT to beige/brite mature adipocytes and exert upregulation of UCP1 [23]. Another PPARγ-signaling affecting drug, PPARγ antagonist Gleevec has been demonstrated to significantly increase brown/beige fat thermogenic and mitochondrial genes, including Ucp-1, Pgc-1α, and cox-5b in WAT and interscapular BAT in mice [11]. Slit 2 derived secretory product, a member of the Slit extracellular protein family, has been demonstrated to regulate beige adipocyte induction via Prdm16 and robust activation of PKA signaling. Slit2-C fragment has an active thermogenic property having an effect on energy expenditure, and glucose homeostasis in vivo [73]. Artepillin C (ArtC) has been demonstrated to induce brown-like adipocytes in mice and primary inguinal WAT-derived adipocytes in vitro through PPARγ and PRDM16 signaling [54].
Adrenomedullin 2 (AM2) has been demonstrated to induce browning of rat primary adipocytes in vitro along with the variety of metabolism ameliorating effects through PGC1α and PRDM16 signaling [93]. Beta-lapachone (BLC) has been reported with the ability to stimulate browning of WAT, increase expression of UCP1, and ameliorate metabolic parameters of mice fed a high-fat diet. The effects of BLC were partially controlled via the regulation of miR-382 targeting deionidase iodothyronine type II (Dio2), but the overall mechanism remains unclear [12].
Inflammatory factors
In a setting of post burn injury, bone marrow originated interleukin 6 (IL-6) has been demonstrated to regulate WAT browning [1]. Interleukin 4 (IL-4) has been reported with a role in BAT activation responding to cold exposure in a macrophage-dependent manner [53]. In addition, deficiency of immediate early response gene X-1 (IEX-1), a downstream effector of Nf-Kb signaling pathway, was demonstrated to induce browning and activate thermogenic gene program in WAT through promotion of alternative activation of adipose macrophages [69].
Hormonal factors
Many different hormones released from variety of organs also exert a crosstalk with adipose tissue physiology and related processes. Thyroid hormones are well known to be able to induce WAT browning through both peripheral and central mechanisms [87]. Triiodothyronine (T3) metabolite triiodothyracetic acid (TRIAC) has been demonstrated with the ability to regulate WAT browning process and induce ectopic expression of UCP1 in abdominal WAT depot of rats [48]. In human cell culture model, T3 treatment enhanced UCP1 expression and mitochondrial biogenesis in human adipose-derived stem cells [37]. Circulating T4 levels have been shown to correspond to UCP1 expression in WAT in humans [47]. While deionidase type II (Dio2) is a key enzyme regulating thyroid hormone signaling and plays a crucial role in thyroid-hormone-related activation of BAT, it is also suggested to be one of the major players in thyroid hormone induced WAT browning [86]. Parathyroid hormone (PTHr) and tumor-derived parathyroid hormone-related protein (PTHrP) has been demonstrated to lead WAT browning in cancer-cachexia models studied in mice [32, 75]. Glucagon-like peptide 1 (GLP1) has been demonstrated to stimulate BAT thermogenesis and adipocyte browning in mice [5, 44]. Leptin together with insulin has been reported to drive WAT browning and weight loss through action on hypothalamic neurons [16]. Melatonin induces browning of WAT in inguinal WAT of rats as observed by increased expression of PGC-1α and UCP-1 [28]. Natriuretic peptides (NPs), endocrine hormones released from the heart, are demonstrated to possess WAT browning capacity and effect on BAT metabolism through several different pathways [6, 42].
Genetic factors
A set of genes have been associated with WAT browning including PTEN, Cox2, Foxc2, folliculin, and Gq. Expression of Gq, a type of G protein-coupled receptor in human WAT, has been demonstrated to inversely correlate with UCP1 expression [33]. Modulation of TGF-β/Smad3 signaling is proposed to activate a brown adipocyte like phenotype in rodent WAT [90].
Batokines
Batokines, such as fibroblast growth factor 21 (FGF21), interleukin 6 (IL-6), and prostaglandin D2 synthase (PTGDS), have been demonstrated to regulate glycaemia and metabolism in animal models by further enhancing glucose and lipid clearance [59, 79]. Fisher et al. demonstrated that in addition to having ameliorating effect on classical BAT and metabolism, FGF21 expression is also necessary for the cold-induced recruitment of beige adipocytes in WAT. Browning is connected with induction of PGC-1α protein levels having only little effect on mRNA expression. Since circulating levels of FGF21 are not elevated upon cold exposure, it has been suggested that FGF21 exerts its action on adipose tissue browning via para- and autocrine mechanisms [20]. However, Keipert and Jastroch demonstrated that FGF21 secreted from muscle acts as an endocrine hormone, targeting other tissues than the tissue of origin. In WAT, FGF21 secreted from skeletal muscle manifests effects that lead to the increased browning of epididymal and subcutaneous fat depots in mice [30]. Apelin, a newly identified adipocyte-derived hormone that is secreted by both brown and white adipocytes, stimulates adipose browning [74]. In their studies, Than et al. demonstrated that apelin increases the activity of BAT, induces browning of WAT, and stimulates metabolic activity both in vitro and in vivo [74].
Exercise
Capability of exercise to induce browning has been a controversial issue. Older studies in humans and rodents report negative results for BAT activation and browning in response to exercise [68, 72, 82]. However, exercise has also been demonstrated to increase expression of PGC-1α [80, 89] and a recently identified exercise adipomyokine irisin has been shown to induce browning in human and rodents [7, 39]. Irisin is cleaved from fibronectin type III domain-containing protein 5 (FNDC5) expressed on the surface of skeletal muscle and WAT, and secreted into circulation. In their studies, Boström et al. demonstrated the browning capability of irisin in in vitro experiments in mouse subcutaneous WAT as well as described the elevated level of plasma irisin in humans in response to exercise [7].
PPAR ligands and signaling
In mice, treatment with PPAR agonists has been demonstrated to increase UCP1 expression in different WAT depots, particularly in the inguinal depot in vivo [22, 36]. In addition, Petrovic et al. demonstrated browning of epididymal WAT depot in mice in response to prolonged treatment with PPARγ agonist rosiglitazone [60]. Study by Ohno et al. (2012) suggested that browning effect of PPAR ligands is centered to stabilization and expression of PRDM16, the main factor controlling classical BAT development [55]. On the other hand, other suggested regulators of PPARγ signaling include α/β-hydrolase domain 6 (ABHD6) that has been demonstrated to negatively regulate adipose tissue browning [95]. In cell culture models of human and mice white adipocytes, a selective PPARα-agonist WY14643 was shown to stimulate mitochondrial biogenesis and UCP1 expression along with the PPAR co-activator PGC-1α [3, 76, 78]. Since PPARγ signaling is one of the main switches in adipocyte development, its involvement in pathways related to WAT browning is highly likely.
BMPs
Bone morphogenetic protein 7 (BMP7) was demonstrated to be able to induce BAT selective genes and induce UPC1 mRNA expression in brown preadipocytes [77]. It also drives the browning of mesenchymal progenitor cells by inducing the expression of PRDM16. This leads to the full activation of BAT gene expression pattern, suggesting that BMP7 is one of the factors determining the cell fate between brown and white [78]. Both BMP7 and BMP4 were demonstrated to induce white-to-brown shifting in primary human adipose stem cells [18]. Bone morphogenetic proteins (BMPs) have been suggested to facilitate adipogenetic differentiation by induction of PRDM16 and PGC-1α [77] and by negatively regulating skeletal myogenesis [71]. The Wingless pathway (Wnt) is crucial in embryonic muscle formation. Activation of this pathway represses brown and white adipogenesis by suppressing the induction of PPARγ and C/EBSα in the precursor cells [64].
Metabolites
Lactate and β-hydroxybutyrate have been demonstrated to increase UCP1 gene expression in human and murine WAT by intracellular redox modifications [8]. Beta-aminoisobutyric acid (BAIBA) has been demonstrated to increase expression of BAT marker genes in WAT of mice both in vitro and in vivo through PPARα-mediated mechanism. In humans, plasma levels of BAIBA are increased with exercise and compound is able to induce BAT-like phenotype in human pluripotent stem cells [63]. Eicosapentaenoic acid has been demonstrated with potential to activate and increase marker gene expression in BAT depots of mice, but no effect on WAT depots has been described [58]. Retinoic acid, a bioactive metabolite of vitamin A, has been reported to induce WAT browning via activating vascular endothelial growth factor (VEGF) signaling in vitro. In co-operation with VEGFA, retinoic acid also was shown to activate p38MAPK signaling pathway and to bind to Prdm16 promoter enhancing its transcription [83].
Concluding remarks
Browning of white adipose tissue has been—and remains to be—an active field of research due to its demonstrated connection and potential to contribute to treatment and prevention of diabetes type 2 and other prevalent metabolic disorders. From the continuously expanding list of novel browning agents, naturally occurring compounds such as metabolites, dietary, hormonal, and stimulated physiological factors hold a special interest due to lack of side effects and non-invasive treatment possibilities of obesity and metabolic disorders.