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• W2079461395 abstract "Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered. Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered. By no means is BAT a novel discovery; the ‘hibernating gland’ was first described in rodents by the Swiss naturalist Conrad Gessner as early as 1551 [1Gessner C. et al.Conradi Gesneri medici Tigurine Historiae Animalium: Lib. I De Quadrupedibus viviparis.1551Google Scholar]. In more recent times throughout the 20th century BAT has been the focus of multiple waves of scientific study, each of which waned as its relevance to adult humans was called into question, largely due to limitations in our ability to measure its presence or activity. The recent resurgence in interest stems from data provided by modern PET-CT imaging studies. Several studies were conducted shortly after Nedergaard et al. published a paper drawing attention to existing metabolic and PET-CT data that supported the existence of active BAT in adult humans [2Nedergaard J. et al.Unexpected evidence for active brown adipose tissue in adult humans.Am. J. Physiol. Endocrinol. Metab. 2007; 293: E444-E452Crossref PubMed Scopus (1377) Google Scholar]. Subsequent PET-CT studies confirmed adipose depots in the supraclavicular region with high labelled glucose uptake rates, which when biopsied expressed high levels of the thermogenic mitochondrial protein, uncoupling protein 1 (UCP1) [3Cypess A.M. et al.Identification and importance of brown adipose tissue in adult humans.N. Engl. J. Med. 2009; 360: 1509-1517Crossref PubMed Scopus (3106) Google Scholar, 4van Marken Lichtenbelt W.D. et al.Cold-activated brown adipose tissue in healthy men.N. Engl. J. Med. 2009; 360: 1500-1508Crossref PubMed Scopus (2563) Google Scholar, 5Virtanen K.A. et al.Functional brown adipose tissue in healthy adults.N. Engl. J. Med. 2009; 360: 1518-1525Crossref PubMed Scopus (2296) Google Scholar, 6Zingaretti M.C. et al.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: 3113-3120Crossref PubMed Scopus (582) Google Scholar]. Some of these studies, and larger retrospective analyses, show that amounts of detectable active BAT are inversely correlated with age, body mass index (BMI), fat mass, and insulin sensitivity [4van Marken Lichtenbelt W.D. et al.Cold-activated brown adipose tissue in healthy men.N. Engl. J. Med. 2009; 360: 1500-1508Crossref PubMed Scopus (2563) Google Scholar, 7Ouellet V. et al.Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans.J. Clin. Endocrinol. Metab. 2011; 96: 192-199Crossref PubMed Scopus (395) Google Scholar]. At the same time, the increased availability of genetically modified murine models has shone more light than ever before on the endogenous mechanisms that exist to regulate BAT function [8Whittle A. Searching for ways to switch on brown fat: are we getting warmer?.J. Mol. Endocrinol. 2012; 49: R79-R87Crossref PubMed Scopus (14) Google Scholar]. Attention has now returned to how we might exploit this tissue more effectively and whether any of these regulatory systems lend themselves to pharmacological or therapeutic intervention. It is posited that increasing the prevalence and activity of BAT might be an effective strategy to treat conditions such as obesity, diabetes, and cardiovascular disease, via increased energy expenditure, the removal of toxic lipid species, and a direct reduction in the demand for insulin production. This review will focus on the latest knowledge surrounding BAT regulation and highlight potential approaches to target thermogenesis safely and effectively. We also discuss situations in which dysregulation of BAT may contribute to certain metabolic diseases. Although views on the prevalence and relevance of BAT in humans have changed dramatically over recent decades, one fact has remained widely undisputed: BAT is under the direct regulation of the sympathetic nervous system, which signals to BAT following exposure to a cold environment (Figure 1). In rodents, increasing caloric intake is also known to activate BAT [9Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (4469) Google Scholar], a phenomenon which is yet to be confirmed in human studies and which will be of great relevance to therapeutic applications of thermogenesis. Following sympathetic stimulation, activation of various isoforms of the β-adrenergic receptors by noradrenaline to induce both the thermogenic activity of existing brown adipocytes and the recruitment of new cells to BAT depots is therefore essential for heat production [9Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance.Physiol. Rev. 2004; 84: 277-359Crossref PubMed Scopus (4469) Google Scholar] (Figure 2). Similarly, intact thyroid hormone signalling is crucial for thermogenesis in BAT, signified by two key observations. Circulating thyroid hormone and BAT levels of the thyroid hormone activating enzyme deiodinase II (DIO2) are strongly increased in situations of increased thermogenesis, and genetic ablation of DIO2 in BAT renders animals incapable of adaptive thermogenesis [10Christoffolete M.A. et al.Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis.Diabetes. 2004; 53: 577-584Crossref PubMed Scopus (167) Google Scholar]. Therefore, when considering strategies to increase BAT thermogenesis, we should be mindful of the necessity to coincidently increase or at least maintain tonic levels of BAT activation by these endogenous regulatory mechanisms. Failure to do so will probably negate the efficacy of approaches targeting more specific aspects of brown adipocyte biology. To understand how to increase the amount of BAT, we must first learn where it comes from. In mouse models, cell lineage tracing has shown fairly conclusively that in development brown adipocytes arise from an origin distinctly different to that of white adipocytes. Interscapular brown adipocytes originate from a cell lineage expressing the myogenic gene Myf5, which are also able to differentiate into skeletal muscle cells [11Timmons J.A. et al.Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 4401-4406Crossref PubMed Scopus (540) Google Scholar]. In BAT, the induction of key transcription factors leads to repression of myogenic gene expression and facilitates brown fat determination. In the past 5 years several factors, including PR domain containing 16 (PRDM16) and Sirtuin 1 (SIRT1), as well as the signals that can induce them, such as bone morphogenetic protein 7 (BMP7), have begun to be identified [11Timmons J.A. et al.Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 4401-4406Crossref PubMed Scopus (540) Google Scholar, 12Seale P. et al.PRDM16 controls a brown fat/skeletal muscle switch.Nature. 2008; 454: 961-967Crossref PubMed Scopus (1656) Google Scholar, 13Tseng Y.H. et al.New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.Nature. 2008; 454: 1000-1004Crossref PubMed Scopus (842) Google Scholar]. Despite their different origins, all adipose tissues are dependent on certain fundamental transcriptional regulators to drive preadipocyte cells towards mature adipocytes, namely peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) [14Farmer S.R. Transcriptional control of adipocyte formation.Cell Metab. 2006; 4: 263-273Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar]. Expression of C/EBPβ, the C/EBP more highly expressed in BAT, and PRDM16 in either human or mouse skin fibroblasts is sufficient to drive these precursors to differentiate into cells displaying the key characteristics of brown adipocytes (expression of UCP1, lipid accumulation, responsiveness to cAMP). Moreover, when transplanted back into mice these genetically modified (GM) fibroblasts formed an ectopic fat pad that appeared and behaved similarly to BAT, taking up labelled glucose to give a positive PET-CT signal [15Kajimura S. et al.Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex.Nature. 2009; 460: 1154-1158Crossref PubMed Scopus (544) Google Scholar]. Obviously there are important differences between mice and humans, a crucial one being our perception of our environmental temperature. In the aforementioned study by Kajimura et al. [15Kajimura S. et al.Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex.Nature. 2009; 460: 1154-1158Crossref PubMed Scopus (544) Google Scholar], the modified BAT-recipient mice were housed at room temperature (20°C–23°C), a sub-thermoneutral temperature for animals of their size. Thermogenic demand would have thus been reasonably high, such that they were driven to activate their additional pool of new BAT. The same temperature constitutes the thermoneutral zone (TNZ) for clothed humans, where they require no additional heat production to maintain their core temperature and therefore very little sympathetic activation of thermogenesis. Given the importance of adrenergic tone to BAT, it is probable that a similar study in humans would have simply seen the extra thermogenic capacity of the transplanted cells largely or even completely unutilised. That said, the study does demonstrate that a population of modified adipocytes, under the right environmental setting, can engraft and acquire adequate vascularisation and innervation to become metabolically active to a significant degree. It should also be mentioned that even when animals are living in the TNZ, the loss of functional BAT via UCP1 ablation renders them susceptible to diet-induced obesity [16Feldmann H.M. et al.UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality.Cell Metab. 2009; 9: 203-209Abstract Full Text Full Text PDF PubMed Scopus (953) Google Scholar], indicating a potential role for thermogenesis in modulating energy expenditure in response to nutritional changes. Also, although GM cell transplants are currently not available for use in humans, they do provide a potential future approach to avoid deleterious off-target effects of a PRDM16-based pharmacological treatment, as very little is known about the effects of factors such as PRDM16 in non-adipose tissues. When mice are exposed to environmental temperatures below their TNZ, over time adaptive thermogenesis is activated and increasing numbers of ‘brown-like’ or ‘beige’ adipocytes appear in traditional white adipose tissue (WAT) depots. These cells are unique in the sense that they express all of the thermogenic machinery but differential levels of several transcription factors [17Petrovic N. et al.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: 7153-7164Crossref PubMed Scopus (1009) Google Scholar]. Importantly, as beige cells arise from WAT progenitor cells they do not express Myf5 as traditional brown adipocytes do [12Seale P. et al.PRDM16 controls a brown fat/skeletal muscle switch.Nature. 2008; 454: 961-967Crossref PubMed Scopus (1656) Google Scholar]. The same ‘browning’ effect is seen in the inguinal WAT of animals treated with agonists of PPARγ [18Crossno Jr, J.T. et al.Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells.J. Clin. Invest. 2006; 116: 3220-3228Crossref PubMed Scopus (210) Google Scholar], and interest in these cells has grown for two key reasons. First, strains of mice that have a higher propensity for ‘browning’ of their white fat show a greater degree of protection from diet-induced obesity when treated with β3-adrenergic receptor agonists [19Collins S. et al.Strain-specific response to β3-adrenergic receptor agonist treatment of diet-induced obesity in mice.Endocrinology. 1997; 138: 405-413Crossref PubMed Scopus (187) Google Scholar] (this is the main receptor isoform regulating thermogenic activity in BAT); and second, it has recently been suggested that the gene expression profile of adult human BAT bears greater resemblance to that of beige adipocytes than murine brown adipocytes found in traditional interscapular depots [20Wu J. et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.Cell. 2012; 150: 366-376Abstract Full Text Full Text PDF PubMed Scopus (2287) Google Scholar]. This finding could be considered encouraging, as traditional BAT depots decline rapidly in childhood and into adolescence, leaving only small residual repositories of thermogenically active tissue by post-pubertal ages [21Symonds M.E. et al.Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children.J. Pediatr. 2012; 161: 892-898Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. In adult mice, beige adipocytes require active induction and recruitment under specific environmental conditions, therefore these human observations at very least suggest that such ‘browning’ mechanisms might remain intact and effective at maintaining a population of thermogenic cells well into later life. When seeking to increase the pool of beige adipocytes in WAT, we may only have to look as far as skeletal muscle. It had been observed that exercise was sufficient to increase the expression of thermogenic genes in WAT, while at the same time protecting mice from the deleterious effects of a high-fat diet [22Xu X. et al.Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011; 300: R1115-R1125Crossref PubMed Scopus (155) Google Scholar]. Subsequently an exercise-induced myokine, namely irisin, has been demonstrated to induce a thermogenic programme of gene expression in WAT, increase energy expenditure, and reduce rates of weight gain in mice [23Bostrom P. et al.A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.Nature. 2012; 481: 463-468Crossref PubMed Scopus (3012) Google Scholar]. At present, this finding should remind people of the multitude of benefits resulting from increased exercise, which also increases circulating irisin levels in humans [24Huh J.Y. et al.FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise.Metabolism. 2012; 61: 1725-1738Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar]. However, before irisin is hailed as a ‘magic switch’ for turning WAT into BAT, there are important points that must be addressed. For example, the irisin receptor remains elusive, and the effects of irisin in other crucial organs have not been examined. A molecule that integrates increased muscle and thermogenic function may also be expected to act on the heart to meet the extra requirements of oxygen provision. In obese individuals already carrying an increased cardiovascular burden, such effects may not be well tolerated. It could also be seen as a paradox for active muscle (which itself generates heat) to further activate thermogenesis in adipose tissues, unless of course exercise induces muscle-based mechanisms associated with shivering, where additional heat production may be required. Other avenues for increasing beige adipocyte content do exist. Trajkovski et al. found that microRNA-133 (miRNA-133) is highly expressed in skeletal muscle and is heavily downregulated in brown and white adipose depots in response to cold exposure in mice [25Trajkovski M. et al.MyomiR-133 regulates brown fat differentiation through Prdm16.Nat. Cell Biol. 2012; 14: 1330-1335Crossref PubMed Scopus (201) Google Scholar]. They also demonstrated that miRNA-133 directly targets PRDM16 to repress its browning effects in adipose tissue and that inhibition of miRNA-133 in BAT or WAT precursor cells allows increased expression of thermogenic genes and increased oxidative metabolism. Given that pharmacological strategies that suppress individual miRNAs have already been tested with some success in humans to treat hepatitis [26Lindow M. Kauppinen S. Discovering the first microRNA-targeted drug.J. Cell Biol. 2012; 199: 407-412Crossref PubMed Scopus (228) Google Scholar], this strategy may also show promise for BAT-centric, anti-obesity therapy. As always there is air for caution. miRNA-133 has recently been identified as an important tumour suppressor [27Moriya Y. et al.Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma.J. Hum. Genet. 2011; 57: 38-45Crossref PubMed Scopus (98) Google Scholar], and its downregulation is associated with cardiac hypertrophy and infarction [28Care A. et al.MicroRNA-133 controls cardiac hypertrophy.Nat. Med. 2007; 13: 613-618Crossref PubMed Scopus (1493) Google Scholar, 29Bostjancic E. et al.MicroRNAs miR-1, miR-133a, miR-133b and miR-208 are dysregulated in human myocardial infarction.Cardiology. 2010; 115: 163-169Crossref PubMed Scopus (257) Google Scholar], perhaps making global pharmacological repression of its expression less than favourable. As discussed above, it is probably of limited benefit to provide an additional pool of thermogenic cells to an individual unless the physiological setting is such that they will receive at least a minimal level of stimulation from the sympathetic nervous system. Similarly, the efficacy of any BAT-expanding approach is likely to be enhanced by parallel strategies to enhance adrenergic stimulation. To this end, bioactive food ingredients such as methylxanthines (caffeine or theophylline), ephedrine, polyphenols (catechins, resveratrol, quercetin, kaempferol), and certain fatty acids or drugs such as sibutramine, which increase or maintain sympathetic nervous system activation, are effective at increasing energy expenditure and lowering body weight [30Dulloo A.G. The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients.Obes. Rev. 2011; 12: 866-883Crossref PubMed Scopus (85) Google Scholar, 31Finer N. et al.Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study.Diabetes Obes. Metab. 2000; 2: 105-112Crossref PubMed Scopus (157) Google Scholar, 32Hansen D.L. et al.Thermogenic effects of sibutramine in humans.Am. J. Clin. Nutr. 1998; 68: 1180-1186PubMed Google Scholar]. However, more recent studies, again using PET-CT, have demonstrated that broad β-adrenergic receptor agonism with isoprenaline or the sympathomimetic ephedrine cannot stimulate BAT glucose uptake in the way that cold exposure does [33Cypess A.M. et al.Cold but not sympathomimetics activates human brown adipose tissue in vivo.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 10001-10005Crossref PubMed Scopus (232) Google Scholar, 34Vosselman M.J. et al.Systemic beta-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans.Diabetes. 2012; 61: 3106-3113Crossref PubMed Scopus (151) Google Scholar]. It should be noted that negative PET-CT results with labelled glucose do not confirm that BAT is inactive; triglycerides are the major fuel source for BAT. However, the fact that sibutramine and other sympathomimetics cannot be targeted to a specific tissue has rendered them unsafe for use in humans anyway [35Torp-Pedersen C. et al.Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial.Eur. Heart J. 2007; 28: 2915-2923Crossref PubMed Scopus (122) Google Scholar]. Attempts to use more specific agonists of β3-adrenergic receptors, which are potent activators of thermogenesis in mice, have had little success in humans. Although both human and rodent isoforms of the β3 receptor respond to specific agonists in adipocytes in vitro [36Soeder K.J. et al.The β3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.J. Biol. Chem. 1999; 274: 12017-12022Crossref PubMed Scopus (161) Google Scholar], in vivo studies had mixed but ultimately disappointing results. Whereas some agonists such as L796568 have been able to induce acute increases in energy expenditure over 24 h following a single dose [37van Baak M.A. et al.Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men.Clin. Pharmacol. Ther. 2002; 71: 272-279Crossref PubMed Scopus (95) Google Scholar], none are able to mediate chronic metabolic alterations. This has been suggested to be due to the small amount of β3-expressing tissues in humans, reduced intracellular signal transduction downstream of the receptor in human adipose tissues, and greater downregulation of receptor expression at the membrane than that observed in rodents [38Larsen T.M. et al.Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men.Am. J. Clin. Nutr. 2002; 76: 780-788Crossref PubMed Scopus (142) Google Scholar]. More recently, researchers are attempting to define more specific physiological mechanisms that regulate the response of BAT to endogenous levels of sympathetic stimulation, with some success. An increasing number of cytokines and hormones have been shown to have positive effects on the thermogenic activity of BAT and perhaps, most interestingly, none of them appear to act via the adrenergic receptors directly but instead through more specific aspects of brown adipocyte biology. Fibroblast growth factor 21 (FGF21) is secreted predominantly by the liver, where levels rise during fasting, feeding a ketogenic diet (high fat, low carbohydrate), or after amino acid deprivation, but also by other tissues such as WAT, BAT, skeletal muscle, and pancreatic β cells following different metabolic signals [39Kharitonenkov A. FGFs and metabolism.Curr. Opin. Pharmacol. 2009; 9: 805-810Crossref PubMed Scopus (115) Google Scholar, 40De Sousa-Coelho A.L. et al.Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation.Biochem. J. 2012; 443: 165-171Crossref PubMed Scopus (181) Google Scholar]. FGF21 appears to regulate metabolic processes in several tissues as part of an adaptive response to starvation but it also improves glucose uptake into adipose tissue and suppresses glucagon production, simultaneously improving insulin sensitivity [41Iglesias P. et al.Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21.Eur. J. Endocrinol. 2012; 167: 301-309Crossref PubMed Scopus (95) Google Scholar]. FGF21 also signals to BAT to increase expression of thermogenic genes and enhance its heat-producing capacity and regulates the browning of WAT through peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) signalling [42Fisher F.M. et al.FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis.Genes Dev. 2012; 26: 271-281Crossref PubMed Scopus (1088) Google Scholar, 43Hondares E. et al.Thermogenic activation induces FGF21 expression and release in brown adipose tissue.J. Biol. Chem. 2011; 286: 12983-12990Crossref PubMed Scopus (436) Google Scholar, 44Hondares E. et al.Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat.Cell Metab. 2010; 11: 206-212Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar]. In line with this, treatment of obese mice with FGF21 is sufficient to reduce body weight by 20%, almost entirely due to increased energy expenditure [45Coskun T. et al.Fibroblast growth factor 21 corrects obesity in mice.Endocrinology. 2008; 149: 6018-6027Crossref PubMed Scopus (804) Google Scholar]. No human studies have been conducted with FGF21 but rhesus monkeys treated with recombinant human FGF21 have also been shown to be protected from diet-induced obesity [46Veniant M.M. et al.Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys.Endocrinology. 2012; 153: 4192-4203Crossref PubMed Scopus (121) Google Scholar]. Paradoxically, circulating levels of FGF21 increase in obesity in humans [47Zhang X. et al.Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.Diabetes. 2008; 57: 1246-1253Crossref PubMed Scopus (682) Google Scholar]. However, further investigations reveal that the same is true in mice and that treatment of obese mice with additional FGF21 brings about markedly reduced activation of FGF21 targets, such as extracellular signal-regulated kinase (ERK)1/2. In light of this, obesity has been suggested to constitute a state of FGF21 resistance, which may go some way to contribute to obesity-associated metabolic complications and perpetuate a state of positive energy balance [48Fisher F.M. et al.Obesity is a fibroblast growth factor 21 (FGF21)-resistant state.Diabetes. 2010; 59: 2781-2789Crossref PubMed Scopus (555) Google Scholar]. Taken together, these findings suggest that FGF21 might be better described as a factor that regulates metabolic changes in multiple tissues in response to alterations in fuel substrate availability. Although the intracellular pathways activated by FGF21 in BAT are unclear its membrane interaction is well characterised. FGF21 signals through traditional FGF receptors conjugated to the membrane protein βKlotho [49Ogawa Y. et al.βKlotho is required for metabolic activity of fibroblast growth factor 21.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 7432-7437Crossref PubMed Scopus (474) Google Scholar], which may offer opportunities to target the thermogenic properties of FGF21 more selectively than other growth factor-activated pathways. We have recently characterised bone morphogenetic protein 8b (BMP8B) as another thermogenically regulated protein, enriched in mature brown adipocytes in line with their level of thermogenic activity [50Whittle A.J. et al.BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions.Cell. 2012; 149: 871-885Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar]. BMP8B is a secretory peptide that acts in an autocrine/paracrine manner to increase the thermogenic capacity of BAT by enhancing the intracellular response to adrenergic stimulation. Mice that lack BMP8B have lower core body temperatures, reduced thermogenic capacity, and are significantly more susceptible to diet-induced obesity due to a reduction in their metabolic rate. Although the precise mechanism of BMP8b action remains unclear, its distinct expression profile of and the high degree of cellular specificity in the BMP receptor system, recently reviewed by Sieber et al. [51Sieber C. et al.Recent advances in BMP receptor signaling.Cytokine Growth Factor Rev. 2" @default.
• W2079461395 created "2016-06-24" @default.
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• W2079461395 date "2013-06-01" @default.
• W2079461395 modified "2023-10-18" @default.
• W2079461395 title "Pharmacological strategies for targeting BAT thermogenesis" @default.
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• W2079461395 doi "https://doi.org/10.1016/j.tips.2013.04.004" @default.
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