Original citation: Hu, Jiamiao and Christian, Mark. (2017) Hormonal factors in the control of the browning of white adipose tissue. Hormone Molecular Biology and Clinical Investigation.

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BAT BAT energy stimulate inhibit normally maintain often hormones involving gut hormones to processes anorexigenic metabolic gut general, hormones and WAT. orexigenic In behavior of while of browning feeding the regulate range system and further BAT nervous a of and central activation axis secrete the the gut-brain to and the signals via therefore, satiety status SNS or nutrients; and nutrient hunger and (CNS) send of energy can absorbs fluctuation hormones gastrointestinal and the Many food homeostasis. sense ingested digests directly that can organ it the is tract gastrointestinal The browning of control the in hormones Gastrointestinal [58]. browning WAT on thermogenesis, BAT glucagon of of independently effect but possible activation, the cold hinting with WAT, glucagon also compared energy of increases magnitude browning glucagon similar that the to a indicates promotes also by found evidence FGF21 expenditure Latest was indirectly. circulating process increased browning supplementation the that secretion glucagon mediate FGF21 demonstrated also may hepatic addition, been enhanced has via In mice it [56]. glucagon-depleted As in rodents [57]. 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WAT dietary of of browning and thermogenesis enhanced as and well inflammation body-wide as selectively gain, production, weight that diet-induced glucose reduced reported hormone hepatic to was endocrine leading intestinal It (FGF15), enteric 15 FXR. induced factor robustly through growth agonist fibroblast acids FXR the gut-restricted bile a For of by expenditure. effects FXR energy intestinal indicates elevate activating date that to processes WAT, research same of the (CpdA) browning activate ligand selective to a likely with or signaling (LCA) cAMP-dependent of As lost acid with activation lithocholic [71]. is Furthermore, or uncoupling CDCA obesity thermogenesis. acids respiratory through bile from the stimulated is protection either effect by acid-mediated adipocytes the themo- brown bile that BAT in activate TGR5 the supporting Importantly, to [70], found mice [69]. been UCP1-knockout bile obesity has in specific against (CDCA) the acid protect chenodeoxycholic through and acid 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adipocytes pathway and brown noradrenaline mature PPAR in and to PRDM16 thermogenesis ness of regulates expression the directly BMP-7 inducing BMP-8b protein example, by For this while activation. preadipocytes and of brown differentiation of members BAT differentiation canonical other the of Several regulators promotes BMP key cells. the as stem identified to mesenchymal also belongs of are BMP-4 family differentiation [100]. the adipocytes in influences manner which organ-autonomous family [100]. an browning in in expression BMP-4 BMP-4 for augments role BRITE important to specifically an precursors suggesting mesenchymal of adipocytes, conversion the stimulates BMP-4 of expression Transgenic ing. inguinal muscle, BAT, in decreased was [98]. expression fat expression UCP1 gonadal as UCP1 and expression of UCP1 enhancement stimulates leptin This that a [98]. confirmed through mice be ob/ob to 4 seems in a BAT WAT with in retroperitoneal adipocytes. weight and white body BAT of the 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(BDNF) factor neurotrophic [93]. mice, derived UCP1 in of secretion expression GH elevated for and required WAT also hormone of a browning treatment affects to hormone, antagonist also GH-releasing leads GH GH of also that or Knockout suggesting [92]. 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J. fat Plutzky brown SH, new Kim the [11] tone: sympathetic beige/brite the resemble Beyond that A. signatures Vidal-Puig F, molecular Villarroya possesses [10] BAT Human al. et L, Ruiz E, Tomoda DW, Scheel H, Ohno K, di昀fferentiated Shinoda vitro LZ, in Sharp in [9] content UCP-1 Reduced al. et hu- DA, and Bertovic MF, mouse Formosa in AK, cell Natoli fat M, Reddy-Luthmoodoo thermogenic C, of Vorlander type AL, distinct Carey a [8] are adipocytes Beige al. et AH, Giang JH, Choi L, Ye LM, adipose P, Sparks white Bostrom in J, Wu progenitors [7] Myf5-lineage myogenic and adipogenic of populations Distinct S. Kuang W, molec- P, Liu tissue: P, Zhang adipose Bi white X, rat Liang T, in Shan adipocytes brown [6] of Occurrence al. et L, Penicaud D, Ricquier S, Raimbault energy on M, Morroni beta 3-agonist, S, Cinti B, athermogenic Cousin [5] CL-316,243, of E昀ffect al. et BL, Waters SS, Lang DJ, Taatjes E, Danforth J, 2010;11:263 Cui Metab. J, Cell Himms-Hagen thermogenesis. [4] diet-induced of myth the and fat LP. Brown Kozak tomography/- [3] emission in positron 18F-flluorodeoxyglucose of uptake fat brown of Patterns in gene BR. 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PLoS obesity. in tissues adipose white subcutaneous human of preadipocytes from derived adipocytes beige/brite 2012;150:366 Cell. man. 2013;54:2214 Res. Lipid J tissues. 1992;103:931 Sci. Cell J characterization. morphological and ular 1994;266:R1371 Physiol. J Am rats. in tissues adipose white and brown and balance 2015;30:320 Med. Nucl J Indian scan. tomography computed 2014;306:E945 Metab. 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Download Date|7/24/17 11:17AM – 64. – 43. uadChristian and Hu 9 γ Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 10 by mimetic FGF21 antidiabetic long-acting novel a of Development al. et K, treat- Retting TF, the P, Osothprarop for Rolzin analog G, FGF21 Chen T, long-acting Ishino potent J, a Huang of [46] engineering Rationale-based al. et T, Hager M, Hall biosynthesisdemon- E, by orthogonal Belouski enabled J, Sun action YS, sustained Li of R, Hecht analogs FGF21 [45] etal. H, Myler Li N, L, sympa- Z, Skidmore via Li fat white browns J, Pinksta昀ff 21 J, factor Mu growth [44] fibroblast Central al. et NL, Nguyen MJ, Chee TI, en- Cisu activity, FM, nerve Fisher sympathetic DM, induce Stevanovic to N, centrally Douris acts [43] FGF21 al. et K, Rahmouni AL, Bookout KC, Coate in DA, Morgan release X, and Ding expression BM, FGF21 Owen induces activation [42] Thermogenic al. et T, Mampel M, Giralt human white FJ, of Gonzalez A, and adipogenesis Giralt R, on browning Iglesias E, e昀ffects Hondares dual [41] exerts Irisin al. et EV, George M, Clare RM, Foss H, Wang protein mitogen-activated C, through Xie Y, adipocytes Zhang white [40] of browning stimulates Irisin al. et Y, Zhao W, Donelan S, Li Y, Meng R, Li Y, development brown-fat-like Zhang drives [39] that myokine PGC1-alpha-dependent A al. et JC, Lo L, Ye tissues A, adipose MP, Korde white Jedrychowski J, of P, Wu browning Bostrom and [38] PGC-1alpha regulates FGF21 al. et F, Verdeguer RJ, regu- Mepani and EC, brain Fox the N, in Douris S, feedback Kleiner hormone thyroid FM, controls Fisher beta [37] receptor X Liver al. et M, Warner B, Huang L, adipose Maneix Y, white Dai to W, brown Wu Y, of Miao profiling [36] expression gene Global al. et K, Kristiansen K, MP, Qvortrup Tygesen R, a Yadav elicits K, receptors Dixen hormone AL, thyroid Basse of [35] activation Pharmacological al. et A, Biter DW, Tinkey DD, Gonzalez SL, Cimini AJ, Martagon JZ, Lin [34] adap- Kl for J, Weiner essential M, is Kranz deiodinase iodothyronine K, 2 Krause type [33] The al. et JW, Harney SW, Kim M, Schneider MO, Ribeiro SD, Carvalho LA, Jesus de [32] and proteins nuclear between interactions vitro In D. Ricquier F, Bouillaud O, Champigny JC, Matamala M, Larose metabolism AM, acid Cassard-Doulcier fatty [31] and AMPK Hypothalamic al. et VR, Velagapudi CR, Gonzalez S, Rodriguez-Cuenca MJ, Vazquez L, Varela M, Lopez [30] Kl M, Kranz J, Weiner Biol [29] Mol Horm tissue. adipose in expression gene protein droplet-associated lipid of a regulation by receptor-mediated tissue Nuclear adipose M. brown Christian human [28] of Activation al. et PA, Kahn SH, Kessler E, Elia Franquet humans C, Roberts-Toler in LS, Weiner tissue AM, adipose Cypess white [27] subcutaneous of Browning al. et T, Chao RS, Radhakrishnan E, Borsheim MK, Saraf C, Porter LS, Sidossis [26] Ren Wouters the A., depresses M. mice Jasper C57BL/6J Jong in de knockout [25] 3-adrenoceptor Beta al. JP, et Giacobino J, Seydoux S, Cinti R, Allevi by beta 3-adrenoceptors G, 2- and Barbatelli M, beta Jimenez 1-, [24] ofbeta activation Di昀fferential M. Lafontan M, thermogen- Berlan nonshivering A, for Bousquet-Melou required C, is Carpene 1 J, protein Galitzky transport [23] acid Fatty al. et A, Falcon B, Tsang AM, Ortegon H, Doege ofbrown M, cultures Kazantzis primary Q, Wu in [22] on UCPsynthesis stimulation beta-adrenoceptor selective of E昀ffect A. Palou MJ, Stock C, P, Pico Puigserver [21] fully are cells fat brown in responses Thermogenic B. Cannon J, Nedergaard A, Jacobsson JM, Fredriksson KB, 2012;5:588 Ohlson Mech. A, Model Matthias Dis glance. [20] a at organ adipose The S. Cinti promotes [19] acid Eicosapentaenoic al. et N, Sainz SM, Ribeiro M, Fernandez-Galilea PL, Prieto-Hontoria S, Lorente-Cebrian LM, beyond. Laiglesia and [18] noradrenaline recruitment: tissue adipose brown in transduction 2007;2007:74364. Signal Res. J. PPAR Nedergaard expression. S, gene Rehnmark proteins A, uncoupling Jacobsson B, of control Cannon the [17] in PPARs M. Giralt R, mito- Iglesias F, the Villarroya of [16] enhancer upstream the in factors transcription Nfe2l2 and protein CREB-binding for motifs LP. Regulatory Kozak JS, Rim [15] agtdcnuaint c昀fl nioy hrao x hr 2013;346:270 Exp Ther. JPharmacol antibody. sca昀ffold a to conjugation targeted 2012;e493457. One. PLoS Diabetes. 2 type of ment 2012;61:505 Diabetes. rodents. in pharmacology antidiabetic enhanced strate 2015;156:2470 Endocrinology. mice. male in action thetic 2014;20:670 Metab. Cell loss. weight and expenditure, ergy 2011;286:12983 Chem. Biol J tissue. adipose brown 2016;311:E530 Metab. Endocrinol Physiol J Am adipocytes. 2014;63:514 Diabetes. signaling. kinase MAP ERK and kinase MAP p38 kinase 2012;481:463 Nature. thermogenesis. and fat white of 2012;26:271 Dev. Genes thermogenesis. adaptive in 2015;112:14006 USA. Sci Acad Natl Proc tissue. adipose white subcutaneous of browning lates 2015;16:215. Geno. 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J Eur fat. white in adipocytes brown of occurrence 1995;9:324 Pharmacol. Clin Fundam adipocytes. brown and white in catecholamines 2006;55:3229 Diabetes. tissue. adipose brown in esis 1996;117:7 Endocrinol. Cell Mol adipocytes. Chem. Biol J thermogenesis. scid-induced fatty or adrenergically in UCP1 2000;275:25073 for substitute not do UCP3 or UCP2 UCP1-dependent. 2016;37:76 Biochem. Nutr J subjects. overweight from adipocytes subcutaneous in features beige-like and biogenesis mitochondrial 1996;20:S36 Disord. Metab Relat Obes J Int 2002;277:34589 Chem. Biol J gene. 1 protein uncoupling chondrial uadChristian and Hu – 58 DOI:10.1152/ajpendo.00437.2016. E518. – 81. ö igN uahA tih昀fK injsE ta.Tyodhroesau ensbonaioetsu activityand tissue adipose brown defines status hormone al. Thyroid et E, Rijntjes K, Steinho昀ff A, Kunath N, ting – 97. ö igN injsE K E, Rijntjes N, ting é .F,Bue ahle annBraa eegadJn ervcNts.The Natasa. 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Ho Physiol JE, thermogenesis. Blevins and [78] adiposity of modulation NPY hypothalamic Dorsomedial S. USA. Sci Bi Acad [77] Natl Proc coculture. in adipocytes and neurons sympathetic between Cross-talk MD. of Lane browning R, suppress Marx to LC, Turtzo neurons AgRP [76] enables transferase O-GlcNAc al. JP, et Singh MD, Li MR, Zimmer ZW, Liu MO, Dietrich HB, Ruan (Lausanne). [75] Endocrinol Front homeostasis. energy and thermogenesis tissue adipose brown of via regulation sensitivity Hypothalamic insulin S. systemic Bi W, control Zhang neurons [74] AgRP al. et K, Timper L, Ruud Engstrom H, obesity Backes reduces I, and Karakasilioti browning J, tissue Ruud adipose SM, promotes Steculorum agonism [73] FXR Intestinal al. et D, Lackey O, Osborn E, Yu SM, Reilly JM, human Suh S, increases Fang acid [72] chenodeoxycholic acid bile The al. et A, Tailleux KH, Roumans B, Brans B, Havekes EB, EP, Nascimento Broeders thermoneu- [71] at expenditure energy stimulate and thermogenesis 1-dependent protein uncoupling induce acids LP. Bile Kozak M, Zietak [70] chenodeoxycholic using thermogenesis fat brown of Enhancement al. AP, et P, Gomes Janovska K, P, Bardova adipose P, tissue. Flachs brown Zouhar JS, Teodoro to interscapular [69] nerve activity onsympathetic enterostatin and galanin of E昀ffect DA. York GA, Bray H, Nagase [68] adipose brown in activity nerve sympathetic suppresses ghrelin CNS administered the Centrally in H. ghrelin Yoshimatsu T, of Kakuma action T, of Masaki T, mechanism Yasuda and [67] distribution The al. et KL, Grove N, Pronchuk M, Tschop S, Diano 2000;407:908 Nature. RG, rodents. Smith in MA, Cowley adiposity [66] induces Ghrelin ML. Heiman DL, Smiley food M, increase Tschop to [65] area tegmental ventral the targets directly Ghrelin SL. Dickson PA, Friberg 2013;27:1120 J. M, Alvarez-Crespo FASEB activity. C, nerve KP, Hansson Skibicka sympathetic [64] tissue adipose brown increases CCK Systemic CJ. Brain Res. Madden tissue. [63] adipose brown to interscapular activity on sympathetic cholecystokinin of E昀ffects GA. sympa- Bray increase M, Egawa to H, system Yoshimatsu nervous [62] central the in acts Amylin K. Rahmouni AF, Russo DF, Guo DA, Morgan Z, thermogenesis Zhang tissue C, adipose Fernandes-Santos brown [61] stimulates agonism GLP-1 al. et F, Villarroya D, Herranz A, Senra R, Gallego ther- M, tissue Imbernon adipose D, brown Beiroa of [60] control Direct al. et C, Veyrat-Durebex DA, Morgan JR, Chabenne N, Chaudhary KM, Heppner indepen- SH, Lockie expenditure [59] energy increases Glucagon al. et AN, Comninos ES, Chambers DB, Thomas C, Coello tissue. C, Izzi-Engbeaya adipose V, brown Salem in [58] thermogenesis adaptive for essential is Glucagon Y. Hayashi Y, Oshida Y, Murata Y, Takagi J N, Am Ozaki thermogenesis. K, and Kinoshita growth [57] tissue adipose brown of stimulation Glucagon of JE. browning Morley AS, the Levine promote J, to Briggs neurons TJ, POMC Bartness on CJ, act Billington insulin [56] and Leptin al. et E, Balland F, Wiede SE, Simonds K, Loh S, Decherf GT, up- Dodd glucose [55] uncouples tissue adipose white of Browning T. Schafmeier S, TP, Herzig Sijmonsma AJ, to Rose interactions A, immune-adipose Vegiopoulos regulates K, that Mossenbock hormone [54] a is Meteorin-like al. et I, Lokurkar J, Lou KJ, JP, Svensson White mus- JZ, in Long FGF21 RR, induces Rao oxidation [53] fat mitochondrial Impaired al. et D, Burk JM, Salbaum S, Ghosh SE, regulation Wicks and JD, MyoD Warfel B, of Vandanmagsar involvement [52] cells: muscle in release and expression FGF21 F. Villarroya M, talk Giralt cross E, the Hondares J, mediating Villarroya by F, homeostasis Ribas glucose [51] maintains FGF21 al. et CR, Triggle SR, Bornstein Y, Wang J, Zhang L, fat Zhong brown Q, promotes Liang GPR120 [50] sensor lipid The al. et A, Gavalda-Navarro M, Cairo p38-MAPK A, a Planavila JV, through Turatsinze adipocytes R, in Cereijo T, expression Quesada-Lopez FGF21 [49] induces Lactate al. et M, Andre M, Ducos E, Arnaud ofthe A, Galinier F, independent Ribas are Y, Jeanson FGF21 of [48] e昀ffects Pharmacologic al. et W, Fan J, Lee R, Komorowski J, Helmering G, Sivits MM, Veniant [47] GRUYTER DE errpr.2008;19:951 Neuroreport. 2015;6:65. 2001;98:12385 2014;159:306 Cell. fat. white 2015;6:136. 2016;165:125 Cell. tissue. adipose brown in expression myostatin 2015;21:159 Med. Nat resistance. insulin and 2015;22:418 Metab. Cell activity. tissue adipose brown 2016;310:E346 Metab. Endocrinol Physiol J Am mice. in trality 2014;38:1027 (Lond). Obes J Int mice. in acid 1996;709:44 Res. Brain 2003;349:75 Lett. Neurosci rats. of tissue 2003;37:649 Neuron. homeostasis. energy regulating circuit hypothalamic novel a demonstrates 2011;180:129 Neuroscience. motivation. 1992;597:298 2013;154:2481 Endocrinology. activity. nerve thetic 2014;63:3346 Diabetes. AMPK. hypothalamic through browning and 2012;61:2753 Diabetes. signaling. receptor peptide-1 glucagon-like system nervous central by mogenesis 2016;18:72 Metab. Obes Diabetes humans. in activation tissue adipose brown of dently 2014;155:3484 Endocrinology. 1987;252:R160 Physiol. 2015;160:88 Cell. fat. white 2014;e1104289. One. PLoS signaling. insulin from take 2014;157:1279 Cell. thermogenesis. fat beige increase 2016;15:1686 Rep. Cell cle. 2014;463:191 J. Biochem signalling. mitochondria-driven by 2014;63:4064 Diabetes. fasting. prolonged during brain and liver between 2016;7:13479. Commun. Nat adipocytes. from release FGF21 and activation 2016;473:685 J. Biochem pathway. 2015;21:731 Metab. Cell tissue. adipose white of – – 303. 90. – – 50. 5. – – – 99. 5. – 104. 17. – 92. – 92. – – 37. 8. – – 34. 65. – 8. – 8. – – 91. 26. – 9. – 54. – 38. – 58. Authenticated |[email protected] author's copy – 75. – 81. – Download Date|7/24/17 11:17AM 13. – 61. – 62. – 5. – 60. uadChristian and Hu – 29. “ Browning 11 ” Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 12 Proc thermogenesis. activate to temperature sense directly cells Fat al. MP, et Jedrychowski MJ, Khandekar L, environmen- P, Kazak with Cohen switch J, Wu fat white-to-brown L, Ye the [112] links VEGF Adipose al. et T, McMurphy A, Slater D, Magee W, Huang pro- X, factor Liu growth MJ, endothelial During vascular [111] of overexpression tissue Adipose al. et S, Munoz S, Tafuro L, Vila T, acclimation. Ferre cold S, Franckhauser during I, tissues Elias adipose [110] in angiogenesis Hypoxia-independent al. et S, Chen S, Lim O, Larsson R, Cao N, in Petrovic Y, expression Xue mRNA factor [109] growth endothelial vascular of activation Adrenergic M. Saito T, Yoshida H, Nikami M, Morimatsu A, with Asano correlates [108] acclimatisation cold a昀tter branching fiber nerve parenchymal Noradrenergic S. Cinti 2013;19:1252 Med. A, Nat Giordano potential. G, therapeutic Barbatelli I, and Murano function [107] development, fat: beige and P. Brown Seale M, homeostasis Harms energy [106] controls Cyclooxygenase-2 al. et A, Ostertag E, Chichelnitskiy I, Schmitt in D, adipocytes Strzoda brown K, of Muller-Decker recruitment A, Vegiopoulos during [105] induction UCP1 al. et Q, Hao I, Bronstad E, Fjaere HH, Lillefosse LM, Pedersen regulatehuman L, Madsen andBMPantagonists [104] BMP4 et al. 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Grammatopoulos H, Lehnert J, Pessin D, Markovic adi- B, human Lu in [84] system hormone Corticotropin-releasing al. et WA, Scherbaum KM, Schulte HS, P, Willenberg Seres SR, Bornstein releasing J, Seres corticotropin of [83] injection central to response in thermogenesis fat brown of Activation MJ. Stock observed cardiomyopathy NJ, Rothwell the RA, prevents LeFeuvre treatment [82] Oxytocin al. et JL, Chiasson TL, Broderick D, Yip BA, Danalache A, Menaouar E, Plante [81] alAa c S.2013;110:12480 USA. Sci Acad Natl 2015;156:2059 Endocrinology. mice. male in stimuli pharmacological and genetic, tal, 2012;61:1801 Diabetes. resistance. insulin and obesity diet-induced against tects 2009;9:99 Metab. Cell 1997;328:179 J. Biochem angiogenesis. cold-induced in implication tissue: adipose brown rat 2009;214:171 Anat. J organ. adipose mouse in density adipocyte brown 2010;328:1158 Sci. adipocytes. brown of recruitment novo de by mice in 2010;5:e11391. One. 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Endocrinol Clin J tissue. pose 1987;26:1217 Neuropharmacology. rat. the in hormone 2015;156:1416 Endocrinology. mice. db/db male diabetic obese in uadChristian and Hu – 71. – 109. – 5. – – 5. 70. – – 81. 21. – 4. – 300. – – 38. – 85. – 807. 28. – – 8. 61. Authenticated |[email protected] author's copy – – 61. 67. – 13. – 73. – 15. – 17. – 83. Download Date|7/24/17 11:17AM – 54. – 25. – – 11. 63. – 9. EGRUYTER DE – 11. Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 13 iga ,M昀fzoiG,Akra E e ,Ei F ole ,e l 昀fc fcrncahei ciiyo rw fat inyoungwomen. brown on activity athletic chronic of E昀ffect et al. R, EliaEF,Woolley H, Lee KE, Ackerman GD, Ma昀ffazioli V, Singhal antiobe- [123] shows pinnatifida, Undaria seaweed, edible from Fucoxanthin K. Miyashita K, Funayama T, Sashima M, Hosokawa humans. H, in Maeda fat [122] body reducing and thermogenesis fat brown activating ingredients food related and Capsinoids T. 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