Brown and Beige Adipose Tissue

Therapy for Obesity and Its Comorbidities?
  • Anny Mulya
    Affiliations
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE40, Cleveland, OH 44195, USA
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  • John P. Kirwan
    Correspondence
    Corresponding author.
    Affiliations
    Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE40, Cleveland, OH 44195, USA

    Department of Nutrition, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA

    Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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      References

        • Ng M.
        • Fleming T.
        • Robinson M.
        • et al.
        Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 766-781
        • Hill J.O.
        • Wyatt H.R.
        • Peters J.C.
        Energy balance and obesity.
        Circulation. 2012; 126: 126-132
        • van Marken Lichtenbelt W.D.
        • Vanhommerig J.W.
        • Smulders N.M.
        • et al.
        Cold-activated brown adipose tissue in healthy men.
        N Engl J Med. 2009; 360: 1500-1508
        • Cypess A.M.
        • Lehman S.
        • Williams G.
        • et al.
        Identification and importance of brown adipose tissue in adult humans.
        N Engl J Med. 2009; 360: 1509-1517
        • Matsushita M.
        • Yoneshiro T.
        • Aita S.
        • et al.
        Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans.
        Int J Obes (Lond). 2014; 38: 812-817
        • Wu J.
        • Bostrom P.
        • Sparks L.M.
        • et al.
        Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.
        Cell. 2012; 150: 366-376
        • Justo R.
        • Oliver J.
        • Gianotti M.
        Brown adipose tissue mitochondrial subpopulations show different morphological and thermogenic characteristics.
        Mitochondrion. 2005; 5: 45-53
        • Aherne W.
        • Hull D.
        Brown adipose tissue and heat production in the newborn infant.
        J Pathol Bacteriol. 1966; 91: 223-234
        • Heaton J.M.
        The distribution of brown adipose tissue in the human.
        J Anat. 1972; 112: 35-39
        • Lean M.E.
        Brown adipose tissue in humans.
        Proc Nutr Soc. 1989; 48: 243-256
        • Virtanen K.A.
        • Lidell M.E.
        • Orava J.
        • et al.
        Functional brown adipose tissue in healthy adults.
        N Engl J Med. 2009; 360: 1518-1525
        • Nedergaard J.
        • Bengtsson T.
        • Cannon B.
        Unexpected evidence for active brown adipose tissue in adult humans.
        Am J Physiol Endocrinol Metab. 2007; 293: E444-E452
        • Orava J.
        • Nuutila P.
        • Lidell M.E.
        • et al.
        Different metabolic responses of human brown adipose tissue to activation by cold and insulin.
        Cell Metab. 2011; 14: 272-279
        • van Marken Lichtenbelt W.D.
        • Schrauwen P.
        Implications of nonshivering thermogenesis for energy balance regulation in humans.
        Am J Physiol Regul Integr Comp Physiol. 2011; 301: R285-R296
        • Rothwell N.J.
        • Stock M.J.
        A role for brown adipose tissue in diet-induced thermogenesis.
        Nature. 1979; 281: 31-35
        • Harms M.
        • Seale P.
        Brown and beige fat: development, function and therapeutic potential.
        Nat Med. 2013; 19: 1252-1263
        • Sharp L.Z.
        • Shinoda K.
        • Ohno H.
        • et al.
        Human BAT possesses molecular signatures that resemble beige/brite cells.
        PLoS One. 2012; 7: e49452
        • Lee P.
        • Werner C.D.
        • Kebebew E.
        • et al.
        Functional thermogenic beige adipogenesis is inducible in human neck fat.
        Int J Obes (Lond). 2014; 38: 170-176
        • Jespersen N.Z.
        • Larsen T.J.
        • Peijs L.
        • et al.
        A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans.
        Cell Metab. 2013; 17: 798-805
        • Shinoda K.
        • Luijten I.H.
        • Hasegawa Y.
        • et al.
        Genetic and functional characterization of clonally derived adult human brown adipocytes.
        Nat Med. 2015; 21: 389-394
        • Atit R.
        • Sgaier S.K.
        • Mohamed O.A.
        • et al.
        Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse.
        Dev Biol. 2006; 296: 164-176
        • Timmons J.A.
        • Wennmalm K.
        • Larsson O.
        • 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: 4401-4406
        • Forner F.
        • Kumar C.
        • Luber C.A.
        • et al.
        Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions.
        Cell Metab. 2009; 10: 324-335
        • Seale P.
        • Bjork B.
        • Yang W.
        • et al.
        PRDM16 controls a brown fat/skeletal muscle switch.
        Nature. 2008; 454: 961-967
        • Petrovic N.
        • Walden T.B.
        • Shabalina I.G.
        • 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: 7153-7164
        • Sanchez-Gurmaches J.
        • Hung C.M.
        • Sparks C.A.
        • et al.
        PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors.
        Cell Metab. 2012; 16: 348-362
        • Long J.Z.
        • Svensson K.J.
        • Tsai L.
        • et al.
        A smooth muscle-like origin for beige adipocytes.
        Cell Metab. 2014; 19: 810-820
        • Xue R.
        • Lynes M.D.
        • Dreyfuss J.M.
        • et al.
        Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes.
        Nat Med. 2015; 21: 760-768
        • Ricquier D.
        • Casteilla L.
        • Bouillaud F.
        Molecular studies of the uncoupling protein.
        FASEB J. 1991; 5: 2237-2242
        • Nicholls D.G.
        • Locke R.M.
        Thermogenic mechanisms in brown fat.
        Physiol Rev. 1984; 64: 1-64
        • Matthias A.
        • Ohlson K.B.
        • Fredriksson J.M.
        • et al.
        Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis.
        J Biol Chem. 2000; 275: 25073-25081
        • Cannon B.
        • Nedergaard J.
        Brown adipose tissue: function and physiological significance.
        Physiol Rev. 2004; 84: 277-359
        • Fedorenko A.
        • Lishko P.V.
        • Kirichok Y.
        Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria.
        Cell. 2012; 151: 400-413
        • Silva J.E.
        Thermogenic mechanisms and their hormonal regulation.
        Physiol Rev. 2006; 86: 435-464
        • Nicholls D.G.
        Hamster brown-adipose-tissue mitochondria. Purine nucleotide control of the ion conductance of the inner membrane, the nature of the nucleotide binding site.
        Eur J Biochem. 1976; 62: 223-228
        • Lowell B.B.
        • Spiegelman B.M.
        Towards a molecular understanding of adaptive thermogenesis.
        Nature. 2000; 404: 652-660
        • van der Lans A.A.
        • Hoeks J.
        • Brans B.
        • et al.
        Cold acclimation recruits human brown fat and increases nonshivering thermogenesis.
        J Clin Invest. 2013; 123: 3395-3403
        • Cao W.
        • Daniel K.W.
        • Robidoux J.
        • et al.
        p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.
        Mol Cell Biol. 2004; 24: 3057-3067
        • Warner A.
        • Mittag J.
        Breaking BAT: can browning create a better white?.
        J Endocrinol. 2016; 228: R19-R29
        • Dodd G.T.
        • Decherf S.
        • Loh K.
        • et al.
        Leptin and insulin act on POMC neurons to promote the browning of white fat.
        Cell. 2015; 160: 88-104
        • Ruan H.B.
        • Dietrich M.O.
        • Liu Z.W.
        • et al.
        O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat.
        Cell. 2014; 159: 306-317
        • Qiu Y.
        • Nguyen K.D.
        • Odegaard J.I.
        • et al.
        Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat.
        Cell. 2014; 157: 1292-1308
        • Brestoff J.R.
        • Kim B.S.
        • Saenz S.A.
        • et al.
        Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.
        Nature. 2015; 519: 242-246
        • Lee M.W.
        • Odegaard J.I.
        • Mukundan L.
        • et al.
        Activated type 2 innate lymphoid cells regulate beige fat biogenesis.
        Cell. 2015; 160: 74-87
        • Lee P.
        • Greenfield J.R.
        Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans.
        Mol Cell Endocrinol. 2015; 418: 184-190
        • Gollisch K.S.
        • Brandauer J.
        • Jessen N.
        • et al.
        Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats.
        Am J Physiol Endocrinol Metab. 2009; 297: E495-E504
        • Craig B.W.
        • Hammons G.T.
        • Garthwaite S.M.
        • et al.
        Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin.
        J Appl Physiol Respir Environ Exerc Physiol. 1981; 51: 1500-1506
        • Stallknecht B.
        • Vinten J.
        • Ploug T.
        • et al.
        Increased activities of mitochondrial enzymes in white adipose tissue in trained rats.
        Am J Physiol. 1991; 261: E410-E414
        • Stanford K.I.
        • Middelbeek R.J.
        • Townsend K.L.
        • et al.
        A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis.
        Diabetes. 2015; 64: 2002-2014
        • Sutherland L.N.
        • Bomhof M.R.
        • Capozzi L.C.
        • et al.
        Exercise and adrenaline increase PGC-1{alpha} mRNA expression in rat adipose tissue.
        J Physiol. 2009; 587: 1607-1617
        • Trevellin E.
        • Scorzeto M.
        • Olivieri M.
        • et al.
        Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms.
        Diabetes. 2014; 63: 2800-2811
        • Boström P.
        • Wu J.
        • Jedrychowski M.P.
        • et al.
        A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.
        Nature. 2012; 481: 463-468
        • Cao L.
        • Choi E.Y.
        • Liu X.
        • et al.
        White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis.
        Cell Metab. 2011; 14: 324-338
        • Lee P.
        • Linderman J.D.
        • Smith S.
        • et al.
        Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans.
        Cell Metab. 2014; 19: 302-309
        • Daskalopoulou S.S.
        • Cooke A.B.
        • Gomez Y.H.
        • et al.
        Plasma irisin levels progressively increase in response to increasing exercise workloads in young, healthy, active subjects.
        Eur J Endocrinol. 2014; 171: 343-352
        • Hew-Butler T.
        • Landis-Piwowar K.
        • Byrd G.
        • et al.
        Plasma irisin in runners and nonrunners: no favorable metabolic associations in humans.
        Physiol Rep. 2015; 3: e12262
        • Norheim F.
        • Langleite T.M.
        • Hjorth M.
        • et al.
        The effects of acute and chronic exercise on PGC-1alpha, irisin and browning of subcutaneous adipose tissue in humans.
        FEBS J. 2014; 281: 739-749
        • Ellefsen S.
        • Vikmoen O.
        • Slettalokken G.
        • et al.
        Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women.
        Eur J Appl Physiol. 2014; 114: 1875-1888
        • Vosselman M.J.
        • Hoeks J.
        • Brans B.
        • et al.
        Low brown adipose tissue activity in endurance-trained compared with lean sedentary men.
        Int J Obes (Lond). 2015; 39: 1696-1702
        • Qiu S.
        • Cai X.
        • Sun Z.
        • et al.
        Chronic exercise training and circulating Irisin in adults: a meta-analysis.
        Sports Med. 2015; 45: 1577-1588
        • Raschke S.
        • Elsen M.
        • Gassenhuber H.
        • et al.
        Evidence against a beneficial effect of irisin in humans.
        PLoS One. 2013; 8: e73680
        • Roca-Rivada A.
        • Castelao C.
        • Senin L.L.
        • et al.
        FNDC5/irisin is not only a myokine but also an adipokine.
        PLoS One. 2013; 8: e60563
        • Palacios-Gonzalez B.
        • Vadillo-Ortega F.
        • Polo-Oteyza E.
        • et al.
        Irisin levels before and after physical activity among school-age children with different BMI: a direct relation with leptin.
        Obesity (Silver Spring). 2015; 23: 729-732
        • Pardo M.
        • Crujeiras A.B.
        • Amil M.
        • et al.
        Association of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index.
        Int J Endocrinol. 2014; 2014: 857270
        • Viitasalo A.
        • Agren J.
        • Venalainen T.
        • et al.
        Association of plasma fatty acid composition with plasma irisin levels in normal weight and overweight/obese children.
        Pediatr Obes. 2015; ([Epub ahead of print])
        • Steensberg A.
        • van Hall G.
        • Osada T.
        • et al.
        Klarlund Pedersen B. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.
        J Physiol. 2000; 529: 237-242
        • Wolsk E.
        • Mygind H.
        • Grondahl T.S.
        • et al.
        IL-6 selectively stimulates fat metabolism in human skeletal muscle.
        Am J Physiol Endocrinol Metab. 2010; 299: E832-E840
        • Knudsen J.G.
        • Murholm M.
        • Carey A.L.
        • et al.
        Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue.
        PLoS One. 2014; 9: e84910
        • Rao R.R.
        • Long J.Z.
        • White J.P.
        • et al.
        Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.
        Cell. 2014; 157: 1279-1291
        • Carriere A.
        • Jeanson Y.
        • Berger-Muller S.
        • et al.
        Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure.
        Diabetes. 2014; 63: 3253-3265
        • Roberts L.D.
        • Bostrom P.
        • O'Sullivan J.F.
        • et al.
        beta-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors.
        Cell Metab. 2014; 19: 96-108
        • Sakamoto T.
        • Takahashi N.
        • Goto T.
        • et al.
        Dietary factors evoke thermogenesis in adipose tissues.
        Obes Res Clin Pract. 2014; 8: e533-9
        • Lettieri Barbato D.
        • Tatulli G.
        • Vegliante R.
        • et al.
        Dietary fat overload reprograms brown fat mitochondria.
        Front Physiol. 2015; 6: 272
        • Fromme T.
        • Klingenspor M.
        Uncoupling protein 1 expression and high-fat diets.
        Am J Physiol Regul Integr Comp Physiol. 2011; 300: R1-R8
        • Vosselman M.J.
        • Brans B.
        • van der Lans A.A.
        • et al.
        Brown adipose tissue activity after a high-calorie meal in humans.
        Am J Clin Nutr. 2013; 98: 57-64
        • Sadurskis A.
        • Dicker A.
        • Cannon B.
        • et al.
        Polyunsaturated fatty acids recruit brown adipose tissue: increased UCP content and NST capacity.
        Am J Physiol. 1995; 269: E351-E360
        • Acheson K.J.
        • Blondel-Lubrano A.
        • Oguey-Araymon S.
        • et al.
        Protein choices targeting thermogenesis and metabolism.
        Am J Clin Nutr. 2011; 93: 525-534
        • Petzke K.J.
        • Riese C.
        • Klaus S.
        Short-term, increasing dietary protein and fat moderately affect energy expenditure, substrate oxidation and uncoupling protein gene expression in rats.
        J Nutr Biochem. 2007; 18: 400-407
        • Saito M.
        • Yoneshiro T.
        • Matsushita M.
        Food ingredients as anti-obesity agents.
        Trends Endocrinol Metab. 2015; 26: 585-587
        • Saito M.
        • Yoneshiro T.
        Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans.
        Curr Opin Lipidol. 2013; 24: 71-77
        • Choo J.J.
        Green tea reduces body fat accretion caused by high-fat diet in rats through beta-adrenoceptor activation of thermogenesis in brown adipose tissue.
        J Nutr Biochem. 2003; 14: 671-676
        • Lone J.
        • Choi J.H.
        • Kim S.W.
        • et al.
        Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes.
        J Nutr Biochem. 2016; 27: 193-202
        • Wang S.
        • Wang X.
        • Ye Z.
        • et al.
        Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way.
        Biochem Biophys Res Commun. 2015; 466: 247-253
        • Sugita J.
        • Yoneshiro T.
        • Hatano T.
        • et al.
        Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men.
        Br J Nutr. 2013; 110: 733-738
        • Bueter M.
        • Lowenstein C.
        • Olbers T.
        • et al.
        Gastric bypass increases energy expenditure in rats.
        Gastroenterology. 2010; 138: 1845-1853
        • Flancbaum L.
        • Choban P.S.
        • Bradley L.R.
        • et al.
        Changes in measured resting energy expenditure after Roux-en-Y gastric bypass for clinically severe obesity.
        Surgery. 1997; 122: 943-949
        • Faria S.L.
        • Faria O.P.
        • Buffington C.
        • et al.
        Energy expenditure before and after Roux-en-Y gastric bypass.
        Obes Surg. 2012; 22: 1450-1455
        • Rabl C.
        • Rao M.N.
        • Schwarz J.M.
        • et al.
        Thermogenic changes after gastric bypass, adjustable gastric banding or diet alone.
        Surgery. 2014; 156: 806-812
        • Stylopoulos N.
        • Hoppin A.G.
        • Kaplan L.M.
        Roux-en-Y gastric bypass enhances energy expenditure and extends lifespan in diet-induced obese rats.
        Obesity (Silver Spring). 2009; 17: 1839-1847
        • Vijgen G.H.
        • Bouvy N.D.
        • Teule G.J.
        • et al.
        Increase in brown adipose tissue activity after weight loss in morbidly obese subjects.
        J Clin Endocrinol Metab. 2012; 97: E1229-E1233
        • Kirwan J.P.
        • Malin S.K.
        • Kullman E.L.
        • et al.
        Early diabetes remission after gastric bypass surgery is explained by exclusion of the foregut.
        American Diabetes Association, San Francisco (CA)2014
        • Ahmad N.N.
        • Pfalzer A.
        • Kaplan L.M.
        Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity.
        Int J Obes (Lond). 2013; 37: 1553-1559
        • Changchien E.M.
        • Ahmed S.
        • Betti F.
        • et al.
        B-type natriuretic peptide increases after gastric bypass surgery and correlates with weight loss.
        Surg Endosc. 2011; 25: 2338-2343
        • Neinast M.D.
        • Frank A.P.
        • Zechner J.F.
        • et al.
        Activation of natriuretic peptides and the sympathetic nervous system following Roux-en-Y gastric bypass is associated with gonadal adipose tissues browning.
        Mol Metab. 2015; 4: 427-436
        • Frayling T.M.
        • Timpson N.J.
        • Weedon M.N.
        • et al.
        A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
        Science. 2007; 316: 889-894
        • Thorleifsson G.
        • Walters G.B.
        • Gudbjartsson D.F.
        • et al.
        Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.
        Nat Genet. 2009; 41: 18-24
        • Willer C.J.
        • Speliotes E.K.
        • Loos R.J.
        • et al.
        Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.
        Nat Genet. 2009; 41: 25-34
        • Dina C.
        • Meyre D.
        • Gallina S.
        • et al.
        Variation in FTO contributes to childhood obesity and severe adult obesity.
        Nat Genet. 2007; 39: 724-726
        • Fischer J.
        • Koch L.
        • Emmerling C.
        • et al.
        Inactivation of the Fto gene protects from obesity.
        Nature. 2009; 458: 894-898
        • Church C.
        • Moir L.
        • McMurray F.
        • et al.
        Overexpression of Fto leads to increased food intake and results in obesity.
        Nat Genet. 2010; 42: 1086-1092
        • Tews D.
        • Fischer-Posovszky P.
        • Fromme T.
        • et al.
        FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes.
        Endocrinology. 2013; 154: 3141-3151
        • Claussnitzer M.
        • Dankel S.N.
        • Kim K.H.
        • et al.
        FTO obesity variant circuitry and adipocyte browning in humans.
        N Engl J Med. 2015; 373: 895-907
        • Blaxter K.L.
        Energy metabolism in animals and man.
        Cambridge University Press, Cambridge (United Kingdom); New York1989
        • James W.P.
        • Trayhurn P.
        Thermogenesis and obesity.
        Br Med Bull. 1981; 37: 43-48
        • Sims E.A.
        • Danforth Jr., E.
        Expenditure and storage of energy in man.
        J Clin Invest. 1987; 79: 1019-1025
        • Wang Z.
        • O'Connor T.P.
        • Heshka S.
        • et al.
        The reconstruction of Kleiber's law at the organ-tissue level.
        J Nutr. 2001; 131: 2967-2970
        • Muzik O.
        • Mangner T.J.
        • Leonard W.R.
        • et al.
        15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat.
        J Nucl Med. 2013; 54: 523-531
        • Ozguven S.
        • Ones T.
        • Yilmaz Y.
        • et al.
        The role of active brown adipose tissue in human metabolism.
        Eur J Nucl Med Mol Imaging. 2016; 43: 355-361
        • Chondronikola M.
        • Volpi E.
        • Borsheim E.
        • et al.
        Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.
        Diabetes. 2014; 63: 4089-4099
        • Lee P.
        • Smith S.
        • Linderman J.
        • et al.
        Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans.
        Diabetes. 2014; 63: 3686-3698
        • Peirce V.
        • Vidal-Puig A.
        Regulation of glucose homoeostasis by brown adipose tissue.
        Lancet Diabetes Endocrinol. 2013; 1: 353-360
        • Sidossis L.
        • Kajimura S.
        Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis.
        J Clin Invest. 2015; 125: 478-486
        • Hao Q.
        • Yadav R.
        • Basse A.L.
        • et al.
        Transcriptome profiling of brown adipose tissue during cold exposure reveals extensive regulation of glucose metabolism.
        Am J Physiol Endocrinol Metab. 2015; 308: E380-E392
        • Stanford K.I.
        • Middelbeek R.J.
        • Townsend K.L.
        • et al.
        Brown adipose tissue regulates glucose homeostasis and insulin sensitivity.
        J Clin Invest. 2013; 123: 215-223
        • Kharitonenkov A.
        • Shiyanova T.L.
        • Koester A.
        • et al.
        FGF-21 as a novel metabolic regulator.
        J Clin Invest. 2005; 115: 1627-1635
        • Wente W.
        • Efanov A.M.
        • Brenner M.
        • et al.
        Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways.
        Diabetes. 2006; 55: 2470-2478
        • Yilmaz Y.
        • Ones T.
        • Purnak T.
        • et al.
        Association between the presence of brown adipose tissue and non-alcoholic fatty liver disease in adult humans.
        Aliment Pharmacol Ther. 2011; 34: 318-323
        • Rosell M.
        • Kaforou M.
        • Frontini A.
        • et al.
        Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice.
        Am J Physiol Endocrinol Metab. 2014; 306: E945-E964
        • Wang G.X.
        • Zhao X.Y.
        • Meng Z.X.
        • et al.
        The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis.
        Nat Med. 2014; 20: 1436-1443
        • Dai Y.N.
        • Zhu J.Z.
        • Fang Z.Y.
        • et al.
        A case-control study: association between serum neuregulin 4 level and non-alcoholic fatty liver disease.
        Metabolism. 2015; 64: 1667-1673