Endocrine and autocrine/paracrine modulators of brown adipose tissue mass and activity as novel therapeutic strategies against obesity and type 2 diabetes

References

[1] HoekeG, KooijmanS, BoonMR, RensenPC, BerbéeJF. Role of brown fat in lipoprotein metabolism and atherosclerosis. Circ Res. 2016;118:173–82.Search in Google Scholar

[2] CannonB, NedergaardJ. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.Search in Google Scholar

[3] CunninghamDJ, StolwijkJA, WengerCB. Comparative thermoregulatory responses of resting men and women. J Appl Physiol Respir Environ Exerc Physiol. 1978;45:908–15.Search in Google Scholar

[4] LeanME. Brown adipose tissue in humans. Proc Nutr Soc. 1989;48:243–56.Search in Google Scholar

[5] HanyTF, GharehpapaghE, KamelEM, BuckA, Himms-HagenJ, von SchulthessGK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging. 2002;29:1393–8.Search in Google Scholar

[6] SaitoM, Okamatsu-OguraY, MatsushitaM, WatanabeK, YoneshiroT, Nio-KobayashiJ, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009;58:1526–31.Search in Google Scholar

[7] van Marken LichtenbeltWD, VanhommerigJW, SmuldersNM, DrossaertsJM, KemerinkGJ, BouvyND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500–8.Search in Google Scholar

[8] OravaJ, NuutilaP, NoponenT, ParkkolaR, ViljanenT, EnerbäckS, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring). 2013;21:2279–87.Search in Google Scholar

[9] GrundlinghJ, DarganPI, El-ZanfalyM, WoodDM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011;7:205–12.Search in Google Scholar

[10] LarsenTM, ToubroS, van BaakMA, GottesdienerKM, LarsonP, SarisWH, 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;76:780–8.Search in Google Scholar

[11] HarmsM, SealeP. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63.Search in Google Scholar

[12] SidossisLS, PorterC, SarafMK, BørsheimE, RadhakrishnanRS, ChaoT, et al. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab. 2015;22:219–27.Search in Google Scholar

[13] WuJ, BoströmP, SparksLM, YeL, ChoiJH, GiangA-H, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–76.Search in Google Scholar

[14] BartnessTJ, VaughanCH, SongCK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010;34:S36–42.Search in Google Scholar

[15] LeanME, JamesWP, JenningsG, TrayhurnP. Brown adipose tissue in patients with phaeochromocytoma. Int J Obes. 1986;10:219–27.Search in Google Scholar

[16] HadiM, ChenCC, WhatleyM, PacakK, CarrasquilloJA. Brown fat imaging with (18)F-6-fluorodopamine PET/CT, (18)F-FDG PET/CT, and (123)I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma. J Nucl Med. 2007;48:1077–83.Search in Google Scholar

[17] CypessAM, LehmanS, WilliamsG, TalI, RodmanD, GoldfineAB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.Search in Google Scholar

[18] NguyenKD, QiuY, CuiX, GohYP, MwangiJ, DavidT, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480:104–8.Search in Google Scholar

[19] FischerK, RuizHH, JhunK, FinanB, OberlinDJ, van der HeideV, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med. 2017;23:623–30.Search in Google Scholar

[20] Himms-HagenJ, CuiJ, DanforthE, TaatjesDJ, LangSS, WatersBL, et al. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol. 1994;266:R1371–82.Search in Google Scholar

[21] ArchJR. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol. 2002;440:99–107.Search in Google Scholar

[22] van BaakMA, HulGB, ToubroS, AstrupA, GottesdienerKM, DeSmetM, et al. Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther. 2002;71:272–9.Search in Google Scholar

[23] ChappleCR, DvorakV, RadziszewskiP, Van KerrebroeckP, WyndaeleJJ, BosmanB, et al. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. 2013;24:1447–58.Search in Google Scholar

[24] CypessAM, WeinerLS, Roberts-TolerC, Franquet ElíaE, KesslerSH, KahnPA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015;21:33–8.Search in Google Scholar

[25] RoseAJ, VegiopoulosA, HerzigS. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations. J Steroid Biochem Mol Biol. 2010;122:10–20.Search in Google Scholar

[26] de GuiaRM, RoseAJ, HerzigS. Glucocorticoid hormones and energy homeostasis. Horm Mol Biol Clin Investig. 2014;19:117–28.Search in Google Scholar

[27] MacfarlaneDP, ForbesS, WalkerBR. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol. 2008;197:189–204.Search in Google Scholar

[28] GlassB, UharekL, GassmannW, FocksB, BolouriH, LoefflerH, et al. Graft-versus-leukemia activity after bone marrow transplantation does not require graft-versus-host disease. Ann Hematol. 1992;64:255–9.Search in Google Scholar

[29] van den BeukelJC, GrefhorstA, QuartaC, SteenbergenJ, MastroberardinoPG, LombèsM, et al. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone. FASEB J. 2014;28:4857–67.Search in Google Scholar

[30] HardwickAJ, LintonEA, RothwellNJ. Thermogenic effects of the antiglucocorticoid RU-486 in the rat: involvement of corticotropin-releasing factor and sympathetic activation of brown adipose tissue. Endocrinology. 1989;124:1684–8.Search in Google Scholar

[31] StrackAM, BradburyMJ, DallmanMF. Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue. Am J Physiol. 1995;268:R183–91.Search in Google Scholar

[32] KongX, YuJ, BiJ, QiH, DiW, WuL, et al. Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes. 2015;64:393–404.Search in Google Scholar

[33] StimsonRH, AnderssonJ, AndrewR, RedheadDN, KarpeF, HayesPC, et al. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes. 2009;58:46–53.Search in Google Scholar

[34] RamageLE, AkyolM, FletcherAM, ForsytheJ, NixonM, CarterRN, et al. Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab. 2016;24:130–41.Search in Google Scholar

[35] ScotneyH, SymondsME, LawJ, BudgeH, SharkeyD, ManolopoulosKN. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo. Metab Clin Exp. 2017;70:125–32.Search in Google Scholar

[36] OuelletV, Routhier-LabadieA, BellemareW, Lakhal-ChaiebL, TurcotteE, CarpentierAC, 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;96:192–9.Search in Google Scholar

[37] LizcanoF, GuzmánG. Estrogen deficiency and the origin of obesity during menopause. Biomed Res Int. 2014;2014:757461.Search in Google Scholar

[38] Nadal-CasellasA, ProenzaAM, LladóI, GianottiM. Effects of ovariectomy and 17-β estradiol replacement on rat brown adipose tissue mitochondrial function. Steroids. 2011;76:1051–6.Search in Google Scholar

[39] Martínez de MorentinPB, González-GarcíaI, MartinsL, LageR, Fernández-MalloD, Martínez-SánchezN, et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 2014;20:41–53.Search in Google Scholar

[40] RodriguezAM, MonjoM, RocaP, PalouA. Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. Cell Mol Life Sci. 2002;59:1714–23.Search in Google Scholar

[41] Rodriguez-CuencaS, MonjoM, FronteraM, GianottiM, ProenzaAM, RocaP. Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status. Cell Physiol Biochem. 2007;20:877–86.Search in Google Scholar

[42] YuanX, HuT, ZhaoH, HuangY, YeR, LinJ, et al. Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc Natl Acad Sci USA. 2016;113:2708–13.Search in Google Scholar

[43] GambineriA, PelusiC, GenghiniS, Morselli-LabateAM, CacciariM, PagottoU, et al. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2004;60:241–9.Search in Google Scholar

[44] BroedersEP, VijgenGH, HavekesB, BouvyND, MottaghyFM, KarsM. Thyroid hormone activates brown adipose tissue and increases non-shivering thermogenesis--a cohort study in a group of thyroid carcinoma patients. PLoS One. 2016;11:e0145049.Search in Google Scholar

[45] RaymondjeanM, DeferN, TichonickyL, KruhJ, KneipB, Guguen-GuillouzoC. Changes in poly (A) + RNA translational pattern during chemically induced hepatocarcinogenesis. Carcinogenesis. 1985;6:1797–803.Search in Google Scholar

[46] ZhangQ, MiaoQ, YeH, ZhangZ, ZuoC, HuaF, et al. The effects of thyroid hormones on brown adipose tissue in humans: a PET-CT study. Diabetes Metab Res Rev. 2014;30:513–20.Search in Google Scholar

[47] BiancoAC, SilvaJE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest. 1987;79:295–300.Search in Google Scholar

[48] RibeiroMO, CarvalhoSD, SchultzJJ, ChielliniG, ScanlanTS, BiancoAC, et al. Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific. J Clin Invest. 2001;108:97–105.Search in Google Scholar

[49] Arrojo E DrigoR, BiancoAC. Type 2 deiodinase at the crossroads of thyroid hormone action. Int J Biochem Cell Biol. 2011;43:1432–41.Search in Google Scholar

[50] HernándezA, ObregónMJ. Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes. Am J Physiol Endocrinol Metab. 2000;278:E769–77.Search in Google Scholar

[51] BaxterJD, WebbP. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov. 2009;8:308–20.Search in Google Scholar

[52] CastilloM, FreitasBC, RoseneML, DrigoRA, GrozovskyR, MacielRM, et al. Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity. Thyroid. 2010;20:545–53.Search in Google Scholar

[53] VillicevCM, FreitasFR, AokiMS, TaffarelC, ScanlanTS, MoriscotAS, et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol. 2007;193:21–9.Search in Google Scholar

[54] BryzgalovaG, EffendicS, KhanA, RehnmarkS, BarbounisP, BouletJ, et al. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141. J Steroid Biochem Mol Biol. 2008;111:262–7.Search in Google Scholar

[55] LeeJ-Y, TakahashiN, YasubuchiM, KimY-I, HashizakiH, KimM-J, et al. Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Physiol Cell Physiol. 2012;302:C463–72.Search in Google Scholar

[56] Martínez-SánchezN, Moreno-NavarreteJM, ContrerasC, Rial-PensadoE, FernøJ, NogueirasR, et al. Thyroid hormones induce browning of white fat. J Endocrinol. 2017;232:351–62.Search in Google Scholar

[57] NikamiH, ShimizuY, EndohD, YanoH, SaitoM. Cold exposure increases glucose utilization and glucose transporter expression in brown adipose tissue. Biochem Biophys Res Commun. 1992;185:1078–82.Search in Google Scholar

[58] ShimizuY, NikamiH, TsukazakiK, MachadoUF, YanoH, SeinoY, et al. Increased expression of glucose transporter GLUT-4 in brown adipose tissue of fasted rats after cold exposure. Am J Physiol. 1993;264:E890–5.Search in Google Scholar

[59] WesterterpK. Diet induced thermogenesis. Nutr Metab (Lond). 2004;1:5.Search in Google Scholar

[60] MössenböckK, VegiopoulosA, RoseAJ, SijmonsmaTP, HerzigS, SchafmeierT. Browning of white adipose tissue uncouples glucose uptake from insulin signaling. PLoS One. 2014;9:e110428.Search in Google Scholar

[61] RajanS, ShankarK, BegM, VarshneyS, GuptaA, SrivastavaA, et al. Chronic hyperinsulinemia reduces insulin sensitivity and metabolic functions of brown adipocyte. J Endocrinol. 2016;230:275–90.Search in Google Scholar

[62] KharitonenkovA, ShiyanovaTL, KoesterA, FordAM, MicanovicR, GalbreathEJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35.Search in Google Scholar

[63] HottaY, NakamuraH, KonishiM, MurataY, TakagiH, MatsumuraS, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology. 2009;150:4625–33.Search in Google Scholar

[64] HondaresE, IglesiasR, GiraltA, GonzalezFJ, GiraltM, MampelT, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem. 2011;286:12983–90.Search in Google Scholar

[65] HondaresE, RosellM, GonzalezFJ, GiraltM, IglesiasR, VillarroyaF. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010;11:206–12.Search in Google Scholar

[66] MuiseES, AzzolinaB, KuoDW, El-SherbeiniM, TanY, YuanX, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol. 2008;74:403–12.Search in Google Scholar

[67] PlanavilaA, RedondoI, HondaresE, VinciguerraM, MuntsC, IglesiasR, et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun. 2013;4:20192019.Search in Google Scholar

[68] IzumiyaY, BinaHA, OuchiN, AkasakiY, KharitonenkovA, WalshK. FGF21 is an Akt-regulated myokine. FEBS Lett. 2008;582:3805–10.Search in Google Scholar

[69] GiraltM, Gavaldà-NavarroA, VillarroyaF. Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol. 2015;418:66–73.Search in Google Scholar

[70] VéniantMM, SivitsG, HelmeringJ, KomorowskiR, LeeJ, FanW, et al. Pharmacologic Effects of FGF21 are independent of the “Browning” of white adipose tissue. Cell Metab. 2015;21:731–8.Search in Google Scholar

[71] SammsRJ, SmithDP, ChengCC, AntonellisPP, PerfieldJW, KharitonenkovA, et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 2015;11:991–9.Search in Google Scholar

[72] StraubL, WolfrumC. FGF21, energy expenditure and weight loss – How much brown fat do you need?. Mol Metab. 2015;4:605–9.Search in Google Scholar

[73] HanssenMJ, BroedersE, SammsRJ, VosselmanMJ, van der LansAA, ChengCC, et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep. 2015;5:10275.Search in Google Scholar

[74] WengY, ChabotJR, BernardoB, YanQ, ZhuY, BrennerMB, et al. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. PLoS One. 2015;10:e0119104.Search in Google Scholar

[75] ReitmanML. FGF21 mimetic shows therapeutic promise. Cell Metab. 2013;18:307–9.Search in Google Scholar

[76] SengenèsC, BerlanM, De GlisezinskiI, LafontanM, GalitzkyJ. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J. 2000;14:1345–51.Search in Google Scholar

[77] Chainani-WuN, WeidnerG, PurnellDM, FrendaS, Merritt-WordenT, KempC, et al. Relation of B-type natriuretic peptide levels to body mass index after comprehensive lifestyle changes. Am J Cardiol. 2010;105:1570–6.Search in Google Scholar

[78] BordicchiaM, LiuD, AmriE-Z, AilhaudG, Dessì-FulgheriP, ZhangC, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122:1022–36.Search in Google Scholar

[79] BoströmP, WuJ, JedrychowskiMP, KordeA, YeL, LoJC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8.Search in Google Scholar

[80] JedrychowskiMP, WrannCD, PauloJA, GerberKK, SzpytJ, RobinsonMM, et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 2015;22:734–40.Search in Google Scholar

[81] PerakakisN, TriantafyllouGA, Fernández-RealJM, HuhJY, ParkKH, SeufertJ, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017;13:324–37.Search in Google Scholar

[82] ElsenM, RaschkeS, EckelJ. Browning of white fat: does irisin play a role in humans?. J Endocrinol. 2014;222:R25–38.Search in Google Scholar

[83] ZhangY, LiR, MengY, LiS, DonelanW, ZhaoY, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014;63:514–25.Search in Google Scholar

[84] RaoRR, LongJZ, WhiteJP, SvenssonKJ, LouJ, LokurkarI, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014;157:1279–91.Search in Google Scholar

[85] VillarroyaF, CereijoR, VillarroyaJ, GiraltM. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 2017;13:26–35.Search in Google Scholar

[86] GnadT, ScheiblerS, von KügelgenI, ScheeleC, KilićA, GlödeA, et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature. 2014;516:395–9.Search in Google Scholar

[87] TsengY-H, KokkotouE, SchulzTJ, HuangTL, WinnayJN, TaniguchiCM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454:1000–4.Search in Google Scholar

[88] SchulzTJ, HuangTL, TranTT, ZhangH, TownsendKL, ShadrachJL, et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci USA. 2011;108:143–8.Search in Google Scholar

[89] ElsenM, RaschkeS, TennagelsN, SchwahnU, JelenikT, RodenM, et al. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells. Am J Physiol Cell Physiol. 2014;306:C431–40.Search in Google Scholar

[90] GustafsonB, HammarstedtA, HedjazifarS, HoffmannJM, SvenssonP-A, GrimsbyJ, et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes. 2015;64:1670–81.Search in Google Scholar

[91] WhittleAJ, CarobbioS, MartinsL, SlawikM, HondaresE, VázquezMJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149:871–85.Search in Google Scholar

[92] GrefhorstA, van den BeukelJC, van HoutenEL, SteenbergenJ, VisserJA, ThemmenAP. Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice. Biol Sex Differ. 2015;6:7.Search in Google Scholar

[93] MurdoloG, BartoliniD, TortoioliC, PiroddiM, IulianoL, GalliF. Lipokines and oxysterols: novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance. Free Radic Biol Med. 2013;65:811–20.Search in Google Scholar

[94] LynesMD, LeiriaLO, LundhM, BarteltA, ShamsiF, HuangTL, et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med. 2017;23:631–7.Search in Google Scholar

[95] WangG-X, ZhaoX-Y, MengZ-X, KernM, DietrichA, ChenZ, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med. 2014;20:1436–43.Search in Google Scholar

[96] WhittleAJ, JiangM, PeirceV, RelatJ, VirtueS, EbinumaH, et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat Commun. 2015;6:8951.Search in Google Scholar

[97] VirtueS, FeldmannH, ChristianM, TanCY, MasoodiM, DaleM, et al. A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. Diabetes. 2012;61:3139–47.Search in Google Scholar

[98] KlepacK, KilićA, GnadT, BrownLM, HerrmannB, WildermanA, et al. The Gq signalling pathway inhibits brown and beige adipose tissue. Nat Commun. 2016;7:10895.Search in Google Scholar

[99] MauseSF, WeberC. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res. 2010;107:1047–57.Search in Google Scholar

[100] ChenY, BuyelJJ, HanssenMJ, SiegelF, PanR, NaumannJ, et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun. 2016;7:11420.Search in Google Scholar