Interaction of thyroid hormone with brown adipose tissue

 

 Buy Article Permissions and Reprints

Summary

Brown adipose tissue (BAT) plays an important role in regulating core-body temperature in various species including man. [¹⁸F]FDGPET/ CT imaging first revealed the presence of metabolically active BAT depots and that decreased BAT function is associated with various metabolic conditions. Thyroid hormone (TH) in concert with sympathetic nervous system signalling (SNS) stimulates BAT thermogenesis and thyroid disorders result in dysfunctional BAT. Currently, research is focussing not only on BAT regulation but also on browning of white adipose tissue (WAT) to BAT beige adipose tissue (BeAT) in order to develop novel treatments for human obesity and related conditions. While [¹⁸F]FDG-PET/ CT imaging is continuing to provide valuable insights into BAT and BeAT function in health and disease, there is a pressing need to develop alternative radiotracers that reliably track their activity in vivo. As a result it is expected that preclinical micro PET/CT investigations of BAT and BeAT will gain in prominence.

The aim of this short review is to i) describe fundamentals in BAT biology, ii) highlight some of the clinical and preclinical studies performed on humans and rodents with a focus on TH, BAT and PET/CT, and iii) bridge these data with our own studies within the DFG thyroid transact priority program.

Zusammenfassung

Braunes Fettgewebe (BAT) besitzt in der Regulation von Körpertemperatur und Energiebalance eine zentrale Rolle. Durch [¹⁸F]FDG-PET/ CT gelang der Nachweis von metabolisch aktivem BAT bei Erwachsenen, wobei sich im Folgenden zeigte, dass eine verminderte BAT-Aktivität mit verschiedenen metabolischen Veränderungen assoziiert ist. Schilddrüsenhormone (TH) aktivieren BAT gemeinsam mit dem sympathischen Nervensystem, sodass auch Schilddrüsenerkrankungen mit einer BAT-Fehlfunktion einhergehen können und es werden zudem ständig weitere BAT-stimulierende Faktoren identifiziert. Der wissenschaftliche Fokus hat sich im vergangenen Jahrzehnt nicht nur auf das Verständnis der BAT-Regulation gerichtet, sondern auch auf eine Transdifferenzierung von weißem Fettgewebe (WAT) zu beigem Fettgewebe (BeAT), um somit neue Behandlungsoptionen für Adipositas und Adipositas-assoziierte Erkrankungen zu gewinnen. [¹⁸F]FDG-PET/CT ermöglicht hierbei einen Einblick in den BATStoffwechsel, auch wenn weiterhin noch Bedarf an alternativen Tracern besteht, die die BAT- und BeAT-Aktivität in vivo nachweisen können. Infolge dessen wird erwartet, dass präklinische PET/CT-Untersuchungen im Hinblick auf BAT- und BeAT-Funktion an Bedeutung gewinnen.

Wir möchten in dieser übersichtsarbeit i) Einblick in die BAT-Biologie geben, ii) bisherige klinische und präklinische PET/CT- Arbeiten zur Interaktion von TH und BAT vorstellen und iii) diese Arbeiten in Verbindung zu eigenen Studien im Rahmen des DFG-Schwerpunktprogramms thyroid trans act setzen.

^* contributed equally

• References

• 1 Auffret J, Viengchareun S, Carre N. et al. Beige differentiation of adipose depots in mice lacking prolactin receptor protects against high-fat-diet-induced obesity. FASEB J 2012; 26: 3728-3737.
  CrossrefPubMedGoogle Scholar
• 2 Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond) 2010; 34 (Suppl 1) S36-S42.
  CrossrefPubMedGoogle Scholar
• 3 Bostrom P, Wu J, Jedrychowski MP. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463-468.
  CrossrefPubMedGoogle Scholar
• 4 Carey AL, Formosa MF, Van Every B. et al. Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 2013; 56: 147-155.
  CrossrefPubMedGoogle Scholar
• 5 Carter EA, Bonab AA, Paul K. et al. Association of heat production with ¹⁸F-FDG accumulation in murine brown adipose tissue after stress. J Nucl Med 2011; 52: 1616-1620.
  CrossrefPubMedGoogle Scholar
• 6 Chau YY, Bandiera R, Serrels A. et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol 2014; 16: 367-375.
  CrossrefPubMedGoogle Scholar
• 7 Chen M, Chen H, Nguyen A. et al. G(s)alpha deficiency in adipose tissue leads to a lean phenotype with divergent effects on cold tolerance and diet-induced thermogenesis. Cell Metab 2010; 11: 320-330.
  CrossrefPubMedGoogle Scholar
• 8 Chen YC, Cypess AM, Chen YC. et al. Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging. J Nucl Med 2013; 54: 1584-1587.
  CrossrefPubMedGoogle Scholar
• 9 Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat (“USA-Fat”): description on ¹⁸F-FDG PET/CT. J Nucl Med 2003; 44: 170-176.
  PubMedGoogle Scholar
• 10 Cohen P, Levy JD, Zhang Y. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 2014; 156: 304-316.
  CrossrefPubMedGoogle Scholar
• 11 Cypess AM, Chen YC, Sze C. et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci USA 2012; 109: 10001-10005.
  CrossrefPubMedGoogle Scholar
• 12 Cypess AM, Lehman S, Williams G. et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509-1517.
  CrossrefPubMedGoogle Scholar
• 13 Cypess AM, White AP, Vernochet C. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013; 19: 635-639.
  CrossrefPubMedGoogle Scholar
• 14 Enerback S, Jacobsson A, Simpson EM. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997; 387: 90-94.
  CrossrefPubMedGoogle Scholar
• 15 Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009; 9: 203-209.
  CrossrefPubMedGoogle Scholar
• 16 Fisher FM, Kleiner S, Douris N. et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26: 271-281.
  CrossrefPubMedGoogle Scholar
• 17 Gerhart-Hines Z, Feng D, Emmett MJ. et al. The nuclear receptor Rev-erbalpha controls circadian thermogenic plasticity. Nature 2013; 503: 410-413.
  CrossrefPubMedGoogle Scholar
• 18 Guerra C, Koza RA, Yamashita H. et al. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 1998; 102: 412-420.
  CrossrefPubMedGoogle Scholar
• 19 Hankir M, Bueter M, Gsell W. et al. Increased energy expenditure in gastric bypass rats is not caused by activated brown adipose tissue. Obes Facts 2012; 5: 349-358.
  CrossrefPubMedGoogle Scholar
• 20 Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19: 1252-1263.
  CrossrefPubMedGoogle Scholar
• 21 Hutchinson DS, Chernogubova E, Dallner OS. et al. Beta-adrenoceptors, but not alpha-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1. Diabetologia 2005; 48: 2386-2395.
  CrossrefPubMedGoogle Scholar
• 22 Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol 1981; 46: 339-345.
  CrossrefPubMedGoogle Scholar
• 23 Kajimura S, Seale P, Kubota K. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 2009; 460: 1154-1158.
  CrossrefPubMedGoogle Scholar
• 24 Kiefer FW, Vernochet C, O'Brien P. et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 2012; 18: 918-925.
  CrossrefPubMedGoogle Scholar
• 25 Kim MS, Hu HH, Aggabao PC. et al. Presence of brown adipose tissue in an adolescent with severe primary hypothyroidism. J Clin Endocrinol Metab 2014; 99: E1686-E1690.
  CrossrefPubMedGoogle Scholar
• 26 Kozak LP. Brown fat and the myth of diet-induced thermogenesis. Cell Metab 2010; 11: 263-267.
  CrossrefPubMedGoogle Scholar
• 27 Kuji I, Imabayashi E, Minagawa A. et al. Brown adipose tissue demonstrating intense FDG uptake in a patient with mediastinal pheochromocytoma. Ann Nucl Med 2008; 22: 231-235.
  CrossrefPubMedGoogle Scholar
• 28 Lahesmaa M, Orava J, Schalin-Jantti C. et al. Hyperthyroidism increases brown fat metabolism in humans. J Clin Endocrinol Metab 2014; 99: E28-E35.
  CrossrefPubMedGoogle Scholar
• 29 Lean ME, James WP, Jennings G, Trayhurn P. Brown adipose tissue in patients with phaeochromocytoma. Int J Obes 1986; 10: 219-227.
  PubMedGoogle Scholar
• 30 Lopez M, Varela L, Vazquez MJ. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008.
  CrossrefPubMedGoogle Scholar
• 31 Lowell BB, Susulic V, Hamann A. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366: 740-742.
  CrossrefPubMedGoogle Scholar
• 32 Mano-Otagiri A, Ohata H, Iwasaki-Sekino A. et al. Ghrelin suppresses noradrenaline release in the brown adipose tissue of rats. J Endocrinol 2009; 201: 341-349.
  CrossrefPubMedGoogle Scholar
• 33 Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM. et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500-1508.
  CrossrefPubMedGoogle Scholar
• 34 Martinez dM, Scanlan TS, Obregon MJ. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology 2010; 151: 5074-5083.
  CrossrefPubMedGoogle Scholar
• 35 Mirbolooki MR, Constantinescu CC, Pan ML, Mukherjee J. Quantitative assessment of brown adipose tissue metabolic activity and volume using ¹⁸F-FDG PET/CT and β3-adrenergic receptor activation. EJNMMI Res. 2011 1. 30.
  PubMedGoogle Scholar
• 36 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.
  CrossrefPubMedGoogle Scholar
• 37 Nguyen KD, Qiu Y, Cui X. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011; 480: 104-108.
  CrossrefPubMedGoogle Scholar
• 38 Orava J, Nuutila P, Lidell ME. et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011; 14: 272-279.
  CrossrefPubMedGoogle Scholar
• 39 Parysow O, Mollerach AM, Jager V. et al. Low-dose oral propranolol could reduce brown adipose tissue F-18 FDG uptake in patients undergoing PET scans. Clin Nucl Med 2007; 32: 351-357.
  CrossrefPubMedGoogle Scholar
• 40 Peirce V, Vidal-Puig A. Regulation of glucose homoeostasis by brown adipose tissue. Lancet Diabetes Endocrinol 2013; 1: 353-360.
  CrossrefPubMedGoogle Scholar
• 41 Qiu Y, Nguyen KD, Odegaard JI. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 2014; 157: 1292-1308.
  CrossrefPubMedGoogle Scholar
• 42 Quarta C, Lodi F, Mazza R. et al. (11)C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion. Mol Metab 2013; 2: 153-160.
  CrossrefPubMedGoogle Scholar
• 43 Ribeiro MO, Lebrun FL, Christoffolete MA. et al. Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat. Am J Physiol Endocrinol Metab 2000; 279: E314-E322.
  CrossrefPubMedGoogle Scholar
• 44 Saeidi N, Meoli L, Nestoridi E. et al. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science 2013; 341: 406-410.
  CrossrefPubMedGoogle Scholar
• 45 Saito M, Okamatsu-Ogura Y, Matsushita M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58: 1526-1531.
  CrossrefPubMedGoogle Scholar
• 46 Sanchez-Alavez M, Tabarean IV, Osborn O. et al. Insulin causes hyperthermia by direct inhibition of warm-sensitive neurons. Diabetes 2010; 59: 43-50.
  CrossrefPubMedGoogle Scholar
• 47 Schulz TJ, Huang P, Huang TL. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013; 495: 379-383.
  CrossrefPubMedGoogle Scholar
• 48 Seyfried F, le Roux CW, Bueter M. Lessons learned from gastric bypass operations in rats. Obes Facts 2011; 4 (Suppl 1) 3-12.
  PubMedGoogle Scholar
• 49 Seyfried F, Li JV, Miras AD. et al. Urinary phenotyping indicates weight loss-independent metabolic effects of Roux-en-Y gastric bypass in mice. J Proteome Res 2013; 12: 1245-1253.
  CrossrefPubMedGoogle Scholar
• 50 Shi YC, Lau J, Lin Z. et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 2013; 17: 236-248.
  CrossrefPubMedGoogle Scholar
• 51 Shimizu I, Aprahamian T, Kikuchi R. et al. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 2014; 124: 2099-2112.
  CrossrefPubMedGoogle Scholar
• 52 Sjostrom L, Lindroos AK, Peltonen M. et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 2683-2693.
  CrossrefPubMedGoogle Scholar
• 53 Skarulis MC, Celi FS, Mueller E. et al. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab 2010; 95: 256-262.
  CrossrefPubMedGoogle Scholar
• 54 Soderlund V, Larsson SA, Jacobsson H. Reduction of FDG uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging 2007; 34: 1018-1022.
  CrossrefPubMedGoogle Scholar
• 55 Tatsumi M, Engles JM, Ishimori T. et al. Intense ¹⁸F-FDG uptake in brown fat can be reduced pharmacologically. J Nucl Med 2004; 45: 1189-1193.
  PubMedGoogle Scholar
• 56 Virtanen KA, Lidell ME, Orava J. et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518-1525.
  CrossrefPubMedGoogle Scholar
• 57 Visser WE, Friesema EC, Visser TJ. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 2011; 25: 1-14.
  CrossrefPubMedGoogle Scholar
• 58 Vosselman MJ, Brans B, van der Lans AA. et al. Brown adipose tissue activity after a high-calorie meal in humans. Am J Clin Nutr 2013; 98: 57-64.
  CrossrefPubMedGoogle Scholar
• 59 Vosselman MJ, van der Lans AA, Brans B. et al. Systemic beta-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes 2012; 61: 3106-3113.
  CrossrefPubMedGoogle Scholar
• 60 Wang CZ, Wei D, Guan MP, Xue YM. Triiodothyronine regulates distribution of thyroid hormone receptors by activating AMP-activated protein kinase in 3T3-L1 adipocytes and induces uncoupling protein-1 expression. Mol Cell Biochem 2014; 393: 247-254.
  CrossrefPubMedGoogle Scholar
• 61 Wang Q, Zhang M, Ning G. et al. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One 2011; 6: e21006.
  CrossrefPubMedGoogle Scholar
• 62 Whittle AJ, Carobbio S, Martins L. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012; 149: 871-885.
  CrossrefPubMedGoogle Scholar
• 63 Wu C, Cheng W, Xing H. et al. Brown adipose tissue can be activated or inhibited within an hour before ¹⁸F-FDG injection: a preliminary study with microPET. J Biomed Biotechnol 2011; 2011: 159834.
  PubMedGoogle Scholar
• 64 Wu J, Bostrom P, Sparks LM. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366-376.
  CrossrefPubMedGoogle Scholar
• 65 Yoneshiro T, Aita S, Matsushita M. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013; 123: 3404-3408.
  CrossrefPubMedGoogle Scholar
• 66 Zhang QY, Miao Q, Ye HY. et al. The effects of thyroid hormones on brown adipose tissue in humans: a PET-CT study. Diabetes Metab Res Rev 2014; 30: 513-520.
  CrossrefPubMedGoogle Scholar
• 67 Cypess AM, Weiner LS, Roberts-Toler C. et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metabolism 2015; 21: 33-38.
  CrossrefPubMedGoogle Scholar