Increased Brown Adipose Tissue Activity Research Articles

Brown adipocytes from induced pluripotent stem cells-how far have we come?

A global increase in the number of individuals who are either overweight or obese is leading to a higher incidence of type 2 diabetes (T2D). Behavioral interventions for the treatment of obesity have yet to deliver desired outcomes, thus introducing a pressing need for molecular- and cellular-based therapies. Excess energy from food is stored in the form of triglycerides in white adipose tissue, which expands during weight gain and can lead to insulin resistance and T2D. By contrast, brown adipose tissue (BAT) releases energy from metabolic substrates in the form of heat and secretes factors that can reverse metabolic disease by acting systemically. Therefore, the ability to increase BAT activity is a promising approach to improve energy balance and metabolic homeostasis. Methods are now being developed to generate brown adipocytes from human induced pluripotent stem cells (hiPSCs), which would (1) provide an unlimited source of cellular material to study human brown adipogenesis, and (2) could be used to develop drug- and cell-based therapies for the treatment of metabolic complications associated with obesity. This article reviews basic BAT biology and details the current progress toward developing brown adipocytes from hiPSCs.

Phenylbutyrate Ameliorates High-Fat Diet-Induced Obesity via Brown Adipose Tissue Activation.

Obesity, which is characterized by an excessive accumulation of body fat, is one of the critical factors causing metabolic syndrome. Many studies have been performed to identify appropriate agents to control obesity, but toxicity remains a problem. Herein, we identified that phenylbutyrate (PBA), which has been used to treat urea cycle disorder with very low toxicity for a long time, efficiently inhibited high fat-induced body weight gain in a diet-induced obesity mouse model (DIO model). PBA treatment decreased body fat mass and increased lean composition. Moreover, PBA increased brown adipose tissue (BAT) activity by increasing glucose uptake, thereby improving glucose tolerance and insulin tolerance. Interestingly, PBA could induce the expression of liver type phosphofructokinase (PFKL), a key enzyme in the glycolytic pathway, and knocking down PFKL dramatically repressed the expression level of Ucp1 as well as those of Prdm16, Cidea, Pgc1α, and Pparγ, which are marker genes for BAT activation. These results strongly suggested that PBA could increase energy expenditure by increasing BAT activity via the induction of PFKL. Taken together, PBA could be used as a therapeutic agent for people with obesity to prevent the development of metabolic syndrome.

1999-P: Cysteine-Rich Protein 2 (CRIP2) Is a Novel Transcriptional Regulator of Uncoupling Protein 1

Since traditional weight loss strategies have been unsuccessful at slowing the increasing rate of obesity, alternative strategies are in high demand. Brown adipose tissue (BAT) is a thermogenic tissue that efficiently expends energy. Thermogenesis in BAT occurs through the action of uncoupling protein 1 (UCP1). Identifying novel transcriptional regulators of UCP1 may lead to potential targets to increase BAT activity since its expression is under tight transcriptional control. Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is a modified CRISPR/Cas9 methodology that identifies novel transcriptional regulators. EnChIP uses dCas9 (lacks endonuclease activity) and guide RNAs (gRNAs) targeting a specific promoter region. The DNA-bound dCas9 can be immunoprecipitated, and the associated promoter region/transcriptional machinery can be sent for proteomic analysis to identify novel transcriptional regulators. Following β-adrenergic stimulation, which activates UCP1 gene transcription in brown adipocytes, we performed enChIP by using five gRNAs targeting the UCP1 promoter. EnChIP analysis of the UCP1 promoter revealed cysteine-rich protein 2 (CRIP2) as a putative transcriptional regulator of UCP1, which was validated by ChIP-PCR. We demonstrated that knocking down CRIP2 in brown adipocytes significantly decreased β-adrenergic-induced UCP1 expression and heat production. Mechanistically, we demonstrated that following β-adrenergic stimulation, CRIP2 was phosphorylated and translocated from the cytosol to the nucleus, where it interacted with peroxisomal proliferator-activated receptor gamma (PPARγ). Taken together, using the unbiased CRISPR-based enChIP approach, we identify CRIP2 as a novel transcriptional regulator that modulates UCP1 expression in response to β-adrenergic stimulation. These findings pave the foundation for developing new anti-obesity and antidiabetes therapies. Disclosure J. Darcy: None. C. Wang: None. M. Lundh: Employee; Self; Gubra. F. Shamsi: None. M. Lynes: None. T. d'Aprigny: None. B. Emanuelli: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd. Funding National Institutes of Health (R01DK077097, R01DK102898, T32DK007260)

2006-P: The Role of Adipose Tissue-Resident Eosinophils in Adipocyte Metabolism and Whole-Body Energy Homeostasis

Adipose tissue resident eosinophils (AT-EOS) are thought to play a pivotal role in whole-body energy homeostasis. However, the precise role of, and the mechanisms underlying AT-EOS in the regulation of whole-body energy metabolism remains elusive. This is because of the limitations of rodent models which have been genetically engineered to either produce elevated whole-body eosinophils or knock-out models for this hematopoietic lineage. To determine the function of AT-EOS, we generated a transgenic mouse model overexpressing human eotaxin[AV1] 2 (hEo2), which is an eosinophil specific chemokine, under the control of a fat-specific aP2 promoter, to recruit circulating EOS exclusively into adipose (hEo2tg). Compared to wild type (WT) littermates of both genders, hEo2tg mice displayed a significant increase of AT-EOS in multiple AT depots including, perirenal and subcutaneous white adipose tissue (sWAT). However, EOS were not increased in brown adipose tissue (BAT). When fed a high-fat diet (HFD), hEo2tg mice gained less weight (males weight: 45.5 ±0.7g vs. 51 ±0.4g, P<0.01 hEo2tg vs. WT) and adipose tissue (males %fat: 20.8 ±0.2 vs. 31.7 ±0.6, P<0.01 hEo2tg vs. WT) compared to WT. Transgenic mice showed improved glucose tolerance (GTT) compared to WT (males GTT AUC: 300054±121 vs. 320865 ±920, hEo2tg vs. WT P<0.001). This was accompanied by increased energy expenditure and heat production compared to WT. These phenotypes were equally found in female animals. Moreover, the adipocytes in hEo2tg were smaller in both genders, and the expression of genes involved in fat oxidation in BAT and sWAT was upregulated in hEo2tg mice compared to WT mice. These data suggest that WAT-resident EOS contribute to increased BAT activation, browning of sWAT and to whole-body energy expenditure. Additional studies will be needed to evaluate the molecular mechanism(s) underling the benefits of AT- EOS. Disclosure T. Li: None. W. LeSuer: None. A. Singh: None. J.D. Hernandez: None. X. Zhang: None. D. Jelinek: None. J. Liu: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc. E.A. Jacobsen: None. E. DeFilippis: None. Funding National Center for Advancing Translational Sciences (KL2TR002379)

Prenylated flavonoid-standardized extract from seeds of Psoralea corylifolia L. activated fat browning in high-fat diet-induced obese mice.

We investigated the effects of the prenylated flavonoid-standardized extract (PFE) from the seeds of Psoralea corylifolia L. on countering obesity, which increases energy expenditure and stimulates thermogenesis in subcutaneous white adipose tissue (sWAT) and brown adipose tissue (BAT). For 12weeks, C57BL/6 mice were fed a controlled high-fat diet (HFD) or HFDs with 0.2% or 0.5% w/w PFE. In vitro, the differentiation of 3T3-L1 cells was used to elicit thermogenesis in the presence of PFE. PFE obviously reduced body weight and fat mass in a dose-dependent manner, increased energy expenditure, improved insulin sensitivity, and prevented hepatic steatosis by increasing lipid oxidation and secretion in HFD-fed mice. Moreover, PFE induced clear browning in sWAT, significantly increased phosphorylation of AMPKα1/2 and p38, increased BAT activity and the differentiation of 3T3-L1 by increasing the expression of uncoupling protein 1 and other thermogenic genes. Our study showed that PFE prevented obesity by increasing browning and activating thermogenic genes in sWAT and BAT, improving glucose homeostasis, and protecting hepatic steatosis.

Octacosanol and policosanol prevent high-fat diet-induced obesity and metabolic disorders by activating brown adipose tissue and improving liver metabolism

Brown adipose tissue (BAT) is an attractive therapeutic target for treating obesity and metabolic diseases. Octacosanol is the main component of policosanol, a mixture of very long chain aliphatic alcohols obtained from plants. The current study aimed to investigate the effect of octacosanol and policosanol on high-fat diet (HFD)-induced obesity. Mice were fed on chow, or HFD, with or without octacosanol or policosanol treatment for four weeks. HFD-fed mice showed significantly higher body weight and body fat compared with chow-fed mice. However, mice fed on HFD treated with octacosanol or policosanol (HFDo/p) showed lower body weight gain, body fat gain, insulin resistance and hepatic lipid content. Lower body fat gain after octacosanol or policosanol was associated with increased BAT activity, reduced expression of genes involved in lipogenesis and cholesterol uptake in the liver, and amelioration of white adipose tissue (WAT) inflammation. Moreover, octacosanol and policosanol significantly increased the expression of Ffar4, a gene encoding polyunsaturated fatty acid receptor, which activates BAT thermogenesis. Together, these results suggest that octacosanol and policosanol ameliorate diet-induced obesity and metabolic disorders by increasing BAT activity and improving hepatic lipid metabolism. Thus, these lipids represent promising therapeutic targets for the prevention and treatment of obesity and obesity-related metabolic disorders.

Simulated microgravity led to increased brown adipose tissue activity in rats

Long-term spaceflight has been proven to induce metabolic dysfunction. Brown adipose tissue (BAT) plays an important role in whole-body energy metabolism. We speculated that BAT function would change under microgravity. Here, we employed a tail suspension (TS) rat model to simulate the effects of microgravity and found that TS increased BAT activity including 1.79, 2.74, 2.69 folds upregulation of UCP1 mRNA at different TS time and induced a phenotypic switch from white adipose tissue (WAT) to brown fat. Furthermore, serum metabolomics revealed abnormal fatty acid metabolism pathway in TS rats. Additionally, we observed that TS led to higher levels of circulating epinephrine (1.28, 1.2, 1.26 folds), norepinephrine (1.12, 1.08, 1.26 folds), adiponectin (1.52, 1.36, 1.64 folds), and FGF21 (2.2, 1.9, 2.7 folds) in different TS rats groups respectively, which contributed to the metabolic disorder in TS rats. In summary, our results indicated that microgravity increased the activity of BAT which might contribute to metabolic dysfunction during long-term exposure to the space environment.

Recent advances in the detection of brown adipose tissue in adult humans: a review.

The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of 18F-fluorodeoxyglucose in combination with computed tomography (18F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative positron emission tomography and computed tomography (PET-CT) imaging strategies and radiotracers that may offer important insights. In addition to PET-CT, there are numerous emerging techniques that may have utility for assessing BAT metabolic activity including magnetic resonance imaging (MRI), skin temperature measurements, near-infrared spectroscopy (NIRS) and contrast ultrasound (CU). In this review, we discuss and critically evaluate the various methodologies used to measure BAT metabolic activity in humans and provide a contemporary assessment of protocols which may be useful in interpreting research findings and guiding the development of future studies.

Brown adipose tissue development and function and its impact on reproduction.

Although brown adipose tissue (BAT) is one of the smallest organs in the body, it has the potential to have a substantial impact on both heat production as well as fat and carbohydrate metabolism. This is most apparent at birth, which is characterised with the rapid appearance and activation of the BAT specific mitochondrial uncoupling protein (UCP)1 in many large mammals. The amount of brown fat then gradually declines with age, an adaptation that can be modulated by the thermal environment. Given the increased incidence of maternal obesity and its potential transmission to the mother's offspring, increasing BAT activity in the mother could be one mechanism to prevent this cycle. To date, however, all rodent studies investigating maternal obesity have been conducted at standard laboratory temperature (21°C), which represents an appreciable cold challenge. This could also explain why offspring weight is rarely increased, suggesting that future studies would benefit from being conducted at thermoneutrality (~28°C). It is also becoming apparent that each fat depot has a unique transcriptome and show different developmental pattern, which is not readily apparent macroscopically. These differences could contribute to the retention of UCP1 within the supraclavicular fat depot, the most active depot in adult humans, increasing heat production following a meal. Despite the rapid increase in publications on BAT over the past decade, the extent to which modifications in diet and/or environment can be utilised to promote its activity in the mother and/or her offspring remains to be established.

The GPR120 agonist TUG‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity.

Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans

Background: The thermogenic effects of green tea catechin have been repeatedly reported, but their mechanisms are poorly understood.Objective: The aim of this study was to investigate the acute and chronic effects of catechin on brown adipose tissue (BAT), a site specialized for nonshivering thermogenesis, in humans.Design: Fifteen healthy male volunteers underwent fluorodeoxyglucose-positron emission tomography to assess BAT activity. To examine the acute catechin effect, whole-body energy expenditure (EE) after a single oral ingestion of a beverage containing 615 mg catechin and 77 mg caffeine (catechin beverage) was measured. Next, to investigate the chronic catechin effects, 10 men with low BAT activity were enrolled. Before and after ingestion of the catechin beverage 2 times/d for 5 wk, cold-induced thermogenesis (CIT) after 2 h of cold exposure at 19°C, which is proportional to BAT activity, was examined. Both the acute and chronic trials were single-blinded, randomized, placebo-controlled, season-matched crossover studies.Results: A single ingestion of the catechin beverage increased EE in 9 subjects who had metabolically active BAT (mean ± SEM: +15.24 ± 1.48 kcal, P < 0.01) but not in 6 subjects who had negligible activities (mean ± SEM: +3.42 ± 2.68 kcal). The ingestion of a placebo beverage containing 82 mg caffeine produced a smaller and comparative EE response in the 2 subject groups. Multivariate regression analysis revealed a significant interaction between BAT and catechin on EE (β = 0.496, P = 0.003). Daily ingestion of the catechin beverage elevated mean ± SEM CIT (from 92.0 ± 26.5 to 197.9 ± 27.7 kcal/d; P = 0.009), whereas the placebo beverage did not change it.Conclusion: Orally ingested tea catechin with caffeine acutely increases EE associated with increased BAT activity and chronically elevates nonshivering CIT, probably because of the recruitment of BAT, in humans. These trials were registered at www.umin.ac.jp/ctr/ as UMIN000016361.

Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats.

Activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) present potential new therapies for obesity and type 2 diabetes. Here, we examined the effects of β3-adrenergic stimulation on tissue-specific uptake and storage of free fatty acids (FFA) and its implications for whole body FFA metabolism in diet-induced obese rats using a multi-radiotracer technique. Male Wistar rats were high fat-fed for 12 wk and administered β3-agonist CL316,243 (CL, 1 mg·kg-1·day-1) or saline via osmotic minipumps during the last 3 wk. The rats were then fasted and acutely infused with a tracer mixture ([14C]palmitate and the partially metabolized R-[3H]bromopalmitate) under anesthesia. CL infusion decreased body weight gain and fasting plasma glucose levels. While core body temperature was unaffected, infrared thermography showed an increase in tail heat dissipation following CL infusion. Interestingly, CL markedly increased both FFA storage and utilization in interscapular and perirenal BAT, whereas the flux of FFA to skeletal muscle was decreased. In this rat model of obesity, only sporadic populations of beige adipocytes were detected in the epididymal WAT depot of CL-infused rats, and there was no change in FFA uptake or utilization in WAT following CL infusion. In summary, β3-agonism robustly increased FFA flux to BAT coupled with enhanced utilization. Increased BAT activation most likely drove the increased tail heat dissipation to maintain thermostasis. Our results emphasize the quantitative role of brown fat as the functional target of β3-agonism in obesity.

Phlorizin treatment attenuates obesity and related disorders through improving BAT thermogenesis

Phlorizin is a member of the chalcone class of organic compounds and was originally extracted from apples. Intensive studies about phlorizin have been conducted. The aim of this study was to determine the therapeutic effects of phlorizin on diet-induced obese mice and to investigate the underlying mechanism. The results show that phlorizin has a beneficial impact on body weight and fat mass, alleviates lipid metabolism and glucose homeostasis. Brown adipose tissue (BAT) temperature was increased and morphological abnormalities were improved in obese mice after phlorizin treatment. Phlorizin activates the Tyk2/STAT3 signalling pathway, up-regulates the protein expression of UCP1, PPARα, PPARγ, C/EBPβ and PRDM16, as well as increases BAT activity which contributes to antiobesity effects. This study suggests that phlorizin activates the Tyk2/STAT3 signalling pathway to induce thermogenesis in BAT and phlorizin has the therapeutic potential in treating obesity and comorbidity.

Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation

SummaryThe discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased 18fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C–17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health.

GQ-16, a TZD-Derived Partial PPARγ Agonist, Induces the Expression of Thermogenesis-Related Genes in Brown Fat and Visceral White Fat and Decreases Visceral Adiposity in Obese and Hyperglycemic Mice.

BackgroundBeige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice.MethodsMale Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content.ResultsGQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT.ConclusionThis study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT.General SignificanceThese findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity.

Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation.

Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by β2-adrenoreceptor (β2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 ± 0.6-fold during β2-AR stimulation using salbutamol infusion in mice (P= 0.003). β2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of β2-AR agonist on brown adipocytes. Finally, β2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 ± 358 vs. 135 ± 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively,P= 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity.

Induction of thermogenesis in brown and beige adipose tissues: molecular markers, mild cold exposure and novel therapies.

The purpose of this short review paper is to summarize recent developments in the understanding of the activation, growth and function of brown adipose tissue (BAT). Transcriptional markers for increased BAT activity and differentiation of white adipocytes to 'beige' or 'brite' adipocytes include amongst others peroxisome proliferator-activated receptor γ, cytosine-enhancer-binding protein, positive regulatory domain 16 and bone morphogenetic proteins. These markers induce uncoupling protein 1 expression in brown and 'beige' or 'brite' adipocytes which allows energy from macronutrients to be expended as heat. Acute and repeated mild cold exposures of 17-19 °C in adult humans increase BAT volume and activity and this is a novel method for increasing their energy expenditure. Emerging evidence suggests that irisin and melatonin hormones may be involved in BAT activation. Additionally, brown adipocyte stem cell therapy transplantation is a means to stimulate this increased thermogenesis from brown and 'beige' or 'brite' adipocytes. Markers for increased BAT activation and for white adipocyte differentiation into beige/brite adipocytes have been identified, and these lead to an uncoupling protein 1-mediated increase in metabolic rate. Mild cold exposure and brown adipocyte stem cell transplantation are two potential strategies for inducing activation and growth of BAT for the treatment of human obesity.

The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity

The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

Can Brown Fat Win the Battle Against White Fat?

A rapid growth in the overweight and obese population in the last few decades suggest that the current diet, exercise, awareness or drug strategies are still not effectively restraining the obesity epidemic. Obesity results from increased energy intake, and the body's energy balance shifts towards energy abundance. Therefore, current research is focused on developing new strategies aimed at increasing energy expenditure. As a result, brown adipose tissue (BAT) is receiving tremendous attention since the major function of BAT is to dissipate energy as heat. For example, mouse models that have increased BAT activity or increased numbers of brown-like adipocytes within the white adipose tissue (WAT) are lean and protected from obesity. Alternatively, mouse models that lack BAT activity are more susceptible to age and diet-induced obesity. However, a significant loss of BAT mass during the natural growth process in humans has created enormous challenges in effectively utilizing this tissue to increase energy expenditure. New strategies are primarily focused on expanding the BAT mass and/or activating the existing BAT. In this regard, recent finding that expression of early B cell factor-2 (Ebf2) reprograms the white pre-adipocytes into brown adipocytes is a significant break-through in developing BAT-mediated strategies to treat obesity. Here we review the major biological functions of WAT and BAT, which play critical but opposing roles in the energy spectrum, energy storage versus energy expenditure, and we evaluate whether activation and/or expansion of BAT is practically achievable to treat obesity in humans.

Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice.

We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet-induced obesity. Metabolic phenotyping was performed using indirect calorimetry in wild-type (WT) and Glp1r-knockout (KO) mice during chow and HFD feeding at room temperature and at thermoneutrality. In a separate study, we investigated the contribution of BAT thermogenic capacity to the weight lowering effect induced by GLP-1 mimetics by administering liraglutide (10 or 30nmolkg(-1)day(-1) s.c.) to diet-induced obese (DIO) mice for 6 or 4weeks, respectively. In both studies, animals were subjected to a noradrenaline (norepinephrine)-stimulated oxygen consumption [Formula: see text] test. At thermoneutrality, HFD-fed Glp1r-KO mice had similar energy expenditure (EE) compared with HFD-fed WT controls. However, HFD-fed Glp1r-KO mice exhibited relatively less EE when housed at a cooler standard room temperature, and had relatively lower [Formula: see text] in response to a noradrenaline challenge, which is consistent with impaired BAT thermogenic capacity. In contrast to the loss of function model, chronic peripheral liraglutide treatment did not increase BAT activity as determined by noradrenaline-stimulated [Formula: see text] and BAT gene expression. These data suggest that although endogenous GLP-1R signalling contributes to increased BAT thermogenesis, this mechanism does not play a significant role in the food intake-independent body weight lowering effect of the GLP-1 mimetic liraglutide in DIO mice.