1932

Abstract

Since the discovery of functionally competent, energy-consuming brown adipose tissue (BAT) in adult humans, much effort has been devoted to exploring this tissue as a means for increasing energy expenditure to counteract obesity. However, despite promising effects on metabolic rate and insulin sensitivity, no convincing evidence for weight-loss effects of cold-activated human BAT exists to date. Indeed, increasing energy expenditure would naturally induce compensatory feedback mechanisms to defend body weight. Interestingly, BAT is regulated by multiple interactions with the hypothalamus from regions overlapping with centers for feeding behavior and metabolic control. Therefore, in the further exploration of BAT as a potential source of novel drug targets, we discuss the hypothalamic orchestration of BAT activity and the relatively unexplored BAT feedback mechanisms on neuronal regulation. With a holistic view on hypothalamic-BAT interactions, we aim to raise ideas and provide a new perspective on this circuit and highlight its clinical relevance.

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2021-02-10
2024-04-20
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Literature Cited

  1. 1. 
    Kim KS, Seeley RJ, Sandoval DA 2018. Signalling from the periphery to the brain that regulates energy homeostasis. Nat. Rev. Neurosci. 19:185–96
    [Google Scholar]
  2. 2. 
    Cannon B, Nedergaard J. 2004. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84:1277–359
    [Google Scholar]
  3. 3. 
    Hanssen MJW, Hoeks J, Brans B, van der Lans AAJJ, Schaart G et al. 2015. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21:86365
    [Google Scholar]
  4. 4. 
    Lee P, Smith S, Linderman J, Courville AB, Brychta RJ et al. 2014. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63:113686–98
    [Google Scholar]
  5. 5. 
    Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T et al. 2013. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Investig. 123:83404–8
    [Google Scholar]
  6. 6. 
    Cypess AM, Weiner LS, Roberts-Toler C, Elía EF, Kessler SH et al. 2015. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 21:133–38
    [Google Scholar]
  7. 7. 
    Blondin DP, Frisch F, Phoenix S, Guérin B, Turcotte ÉE et al. 2017. Inhibition of intracellular triglyceride lipolysis suppresses cold-induced brown adipose tissue metabolism and increases shivering in humans. Cell Metab 25:2438–47
    [Google Scholar]
  8. 8. 
    Carpentier AC, Blondin DP, Virtanen KA, Richard D, Haman F, Turcotte ÉE 2018. Brown adipose tissue energy metabolism in humans. Front. Endocrinol. 9:447
    [Google Scholar]
  9. 9. 
    Himms-Hagen J. 1991. Neural control of brown adipose tissue thermogenesis, hypertrophy, and atrophy. Front. Neuroendocrinol. 12:138–93
    [Google Scholar]
  10. 10. 
    Jaroslawska J, Chabowska-Kita A, Kaczmarek MM, Kozak LP 2015. Npvf: hypothalamic biomarker of ambient temperature independent of nutritional status. PLOS Genet 11:9e1005431
    [Google Scholar]
  11. 11. 
    Jespersen NZ, Feizi A, Andersen ES, Heywood S, Hattel HB et al. 2019. Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells. Mol. Metab. 24:30–43
    [Google Scholar]
  12. 12. 
    Jespersen NZ, Andersen MW, Jensen VH, Staerkaer TW, Severinsen MCK et al. 2020. Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity. bioRxiv 082057 https://doi.org/10.1101/2020.05.07.082057
    [Crossref]
  13. 13. 
    Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T et al. 2009. High incidence of metabolically active brown adipose effects of cold exposure and adiposity. Diabetes 58:1526–31
    [Google Scholar]
  14. 14. 
    Van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ et al. 2009. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360:151500–8
    [Google Scholar]
  15. 15. 
    Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E et al. 2011. 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. 96:1192–99
    [Google Scholar]
  16. 16. 
    Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T et al. 2011. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity 19:91755–60
    [Google Scholar]
  17. 17. 
    Yoneshiro T, Matsushita M, Nakae S, Kameya T, Sugie H et al. 2016. Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310:10R999–1009
    [Google Scholar]
  18. 18. 
    Senn JR, Maushart CI, Gashi G, Michel R, Lalive d'Epinay M et al. 2018. Outdoor temperature influences cold induced thermogenesis in humans. Front. Physiol. 9:1184
    [Google Scholar]
  19. 19. 
    Chen KY, Cypess AM, Laughlin MR, Haft CR, Hu HH et al. 2016. Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans. Cell Metab 24:2210–22
    [Google Scholar]
  20. 20. 
    Cypess AM, Lehman S, Williams G, Tal I, Rodman D et al. 2009. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360:151509–17
    [Google Scholar]
  21. 21. 
    Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R et al. 2009. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360:151518–25
    [Google Scholar]
  22. 22. 
    Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A et al. 2009. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23:93113–20
    [Google Scholar]
  23. 23. 
    Scheele C, Nielsen S. 2017. Metabolic regulation and the anti-obesity perspectives of human brown fat. Redox Biol 12:770–75
    [Google Scholar]
  24. 24. 
    Lowell BB, S-Susulic V, Hamann A, Lawitts JA, Himms-Hagen J et al. 1993. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366:6457740–42
    [Google Scholar]
  25. 25. 
    Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B et al. 2012. Brown adipose tissue oxidative metabolism contributes to energy expenditure during cold exposure in humans. J. Clin. Investig. 122:2545–52
    [Google Scholar]
  26. 26. 
    Hanssen MJW, van der Lans AAJJ, Brans B, Hoeks J, Jardon KMC et al. 2016. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65:51179–89
    [Google Scholar]
  27. 27. 
    O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S et al. 2020. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J. Clin. Investig. 130:52209–19
    [Google Scholar]
  28. 28. 
    Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS et al. 2017. Mapping of human brown adipose tissue in lean and obese young men. PNAS 114:326–11
    [Google Scholar]
  29. 29. 
    Leibel RL, Rosenbaum M, Hirsch J 1995. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332:10621–28
    [Google Scholar]
  30. 30. 
    Blondin DP, Labbé SM, Phoenix S, Guérin B, Turcotte ÉE et al. 2015. Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men. J. Physiol. 593:3701–14
    [Google Scholar]
  31. 31. 
    Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J 2010. Chronic peroxisome proliferator-activated receptor gamma (PPARγ) 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. 285:107153–64
    [Google Scholar]
  32. 32. 
    Seale P, Conroe HM, Estall J, Kajimura S, Frontini A et al. 2011. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Investig. 121:196–105
    [Google Scholar]
  33. 33. 
    Wiedmann NM, Stefanidis A, Oldfield BJ 2017. Characterization of the central neural projections to brown, white, and beige adipose tissue. FASEB J 31:114879–90
    [Google Scholar]
  34. 34. 
    Sanchez-Gurmaches J, Tang Y, Jespersen NZ, Wallace M, Martinez Calejman C et al. 2018. Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab 27:1195–209
    [Google Scholar]
  35. 35. 
    de Jong JMA, Sun W, Pires ND, Frontini A, Balaz M et al. 2019. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat. Metab. 1:8830–43
    [Google Scholar]
  36. 36. 
    Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homøe P et al. 2013. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 17:5798–805
    [Google Scholar]
  37. 37. 
    Heaton JM. 1972. The distribution of brown adipose tissue in the human. J. Anat. 112:Part 135–39
    [Google Scholar]
  38. 38. 
    Wu J, Boström P, Sparks LMM, Ye L, Choi JHH et al. 2012. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:2366–76
    [Google Scholar]
  39. 39. 
    Zhang F, Hao G, Shao M, Nham K, An Y et al. 2018. An adipose tissue atlas: an image-guided identification of human-like BAT and beige depots in rodents. Cell Metab 9:27252–62
    [Google Scholar]
  40. 40. 
    Efremova A, Senzacqua M, Venema W, Isakov E, Di Vincenzo A et al. 2019. A large proportion of mediastinal and perirenal visceral fat of Siberian adult people is formed by UCP1 immunoreactive multilocular and paucilocular adipocytes. J. Physiol. Biochem. 78:185–92
    [Google Scholar]
  41. 41. 
    Søndergaard E, Gormsen LC, Christensen MH, Pedersen SB, Christiansen P et al. 2015. Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue. Diabet. Med. 32:2e4–8
    [Google Scholar]
  42. 42. 
    Frontini A, Vitali A, Perugini J, Murano I, Romiti C et al. 2013. White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1831. 5:950–59
    [Google Scholar]
  43. 43. 
    Lean ME, James WP, Jennings G, Trayhurn P 1986. Brown adipose tissue in patients with phaeochromocytoma. Int. J. Obes. 10:219–227
    [Google Scholar]
  44. 44. 
    Dundamadappa SK, Shankar S, Danrad R, Singh A, Vijayaraghavan G et al. 2007. Imaging of brown fat associated with adrenal pheochromocytoma. Acta Radiol 48:4468–72
    [Google Scholar]
  45. 45. 
    Cao Q, Jing J, Cui X, Shi H, Xue B 2019. Sympathetic nerve innervation is required for beigeing in white fat. Physiol. Rep. 7:6e14031
    [Google Scholar]
  46. 46. 
    Ryu V, Garretson JT, Liu Y, Vaughan CH, Bartness TJ 2015. Brown adipose tissue has sympathetic-sensory feedback circuits. J. Neurosci. 35:52181–90
    [Google Scholar]
  47. 47. 
    Vaughan CH, Bartness TJ. 2012. Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302:9R1049–58
    [Google Scholar]
  48. 48. 
    Caron A, Lee S, Elmquist JK, Gautron L 2018. Leptin and brain-adipose crosstalks. Nat. Rev. Neurosci. 19:3153–65
    [Google Scholar]
  49. 49. 
    François M, Torres H, Huesing C, Zhang R, Saurage C et al. 2019. Sympathetic innervation of the interscapular brown adipose tissue in mouse. Ann. N. Y. Acad. Sci. 1454:13–13
    [Google Scholar]
  50. 50. 
    Nguyen NLT, Barr CL, Ryu V, Cao Q, Xue B, Bartness TJ 2017. Separate and shared sympathetic outflow to white and brown fat coordinately regulates thermoregulation and beige adipocyte recruitment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 312:1R132–45
    [Google Scholar]
  51. 51. 
    Nguyen NLT, Randall J, Banfield BW, Bartness TJ 2014. Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306:6R375–86
    [Google Scholar]
  52. 52. 
    Youngstrom TG, Bartness TJ. 1995. Catecholaminergic innervation of white adipose tissue in Siberian hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 268:3R744–51
    [Google Scholar]
  53. 53. 
    Ryu V, Watts AG, Xue B, Bartness TJ 2017. Bidirectional crosstalk between the sensory and sympathetic motor systems innervating brown and white adipose tissue in male Siberian hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 312:3R324–37
    [Google Scholar]
  54. 54. 
    Fischer AW, Schlein C, Cannon B, Heeren J, Nedergaard J 2019. Intact innervation is essential for diet-induced recruitment of brown adipose tissue. Am. J. Physiol. Endocrinol. Metab. 316:3E487–503
    [Google Scholar]
  55. 55. 
    Li Y, Schnabl K, Gabler SM, Willershäuser M, Reber J et al. 2018. Secretin-activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175:61561–74.e12
    [Google Scholar]
  56. 56. 
    Camerino C, Conte E, Cannone M, Caloiero R, Fonzino A, Tricarico D 2016. Nerve growth factor, brain-derived neurotrophic factor and osteocalcin gene relationship in energy regulation, bone homeostasis and reproductive organs analyzed by mRNA quantitative evaluation and linear correlation analysis. Front. Physiol. 7:456
    [Google Scholar]
  57. 57. 
    Rosell M, Kaforou M, Frontini A, Okolo A, Chan YW et al. 2014. Brown and white adipose tissues: Intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 306:8E945–64
    [Google Scholar]
  58. 58. 
    Pellegrinelli V, Peirce VJ, Howard L, Virtue S, Türei D et al. 2018. Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue. Nat. Commun. 9:14974
    [Google Scholar]
  59. 59. 
    Zeng X, Ye M, Resch JM, Jedrychowski MP, Hu B et al. 2019. Innervation of thermogenic adipose tissue via a calsyntenin 3β-S100b axis. Nature 569:7755229–35
    [Google Scholar]
  60. 60. 
    Garretson JT, Szymanski LA, Schwartz GJ, Xue B, Ryu V, Bartness TJ 2016. Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol. Metab. 5:8626–34
    [Google Scholar]
  61. 61. 
    Chi J, Crane A, Wu Z, Cohen P 2018. Adipo-clear: a tissue clearing method for three-dimensional imaging of adipose tissue. J. Vis. Exp. 2018. 137:58271
    [Google Scholar]
  62. 62. 
    Chi J, Wu Z, Choi CHJ, Nguyen L, Tegegne S et al. 2018. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab 27:1226–236.e3
    [Google Scholar]
  63. 63. 
    Blondin DP, Severinsen MC, Kuipers EN, Jensen VH, Miard S et al. 2019. Human BAT thermogenesis is stimulated by the β2-adrenergic receptor. Cell Metab 32:2287–300
    [Google Scholar]
  64. 64. 
    Deshmukh AS, Peijs L, Beaudry JL, Jespersen NZ, Nielsen CH et al. 2019. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab 30:5963–975
    [Google Scholar]
  65. 65. 
    Scheele C, Wolfrum C. 2019. Brown adipose cross talk in tissue plasticity and human metabolism. Endocr. Rev. 41:153–65
    [Google Scholar]
  66. 66. 
    Clarke IJ. 2015. Hypothalamus as an endocrine organ. Compr. Physiol. 5:1217–53
    [Google Scholar]
  67. 67. 
    Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD 1994. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8:101298–308
    [Google Scholar]
  68. 68. 
    Koch M, Horvath TL. 2014. Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism. Mol. Psychiatry 19:752–61
    [Google Scholar]
  69. 69. 
    Hill JW, Faulkner LD. 2017. The role of the melanocortin system in metabolic disease: new developments and advances. Neuroendocrinology 104:330–46
    [Google Scholar]
  70. 70. 
    Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF 1986. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7:61189–92
    [Google Scholar]
  71. 71. 
    Morton GJ, Schwartz MW. 2001. The NPY/AgRP neuron and energy homeostasis. Int. J. Obes. 25:S56–62
    [Google Scholar]
  72. 72. 
    Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW et al. 2014. Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:4682–93
    [Google Scholar]
  73. 73. 
    Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL 2008. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149:52138–48
    [Google Scholar]
  74. 74. 
    Myers MG, Münzberg H, Leinninger GM, Leshan RL 2009. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab 9:2117–23
    [Google Scholar]
  75. 75. 
    Varela L, Horvath TL. 2012. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:121079–86
    [Google Scholar]
  76. 76. 
    Nakamura K, Morrison SF. 2008. A thermosensory pathway that controls body temperature. Nat. Neurosci. 11:162–71
    [Google Scholar]
  77. 77. 
    Nakamura K, Morrison SF. 2011. Central efferent pathways for cold-defensive and febrile shivering. J. Physiol. 589:143641–58
    [Google Scholar]
  78. 78. 
    Bamshad M, Song CK, Bartness TJ 1999. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 276:6R1569–78
    [Google Scholar]
  79. 79. 
    Song CK, Vaughan CH, Keen-Rhinehart E, Harris RBS, Richard D, Bartness TJ 2008. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295:2R417–28
    [Google Scholar]
  80. 80. 
    Labbé SM, Caron A, Lanfray D, Monge-Rofarello B, Bartness TJ, Richard D 2015. Hypothalamic control of brown adipose tissue thermogenesis. Front. Syst. Neurosci. 9:150
    [Google Scholar]
  81. 81. 
    Andersson B, Larsson B. 1961. Influence of local temperature changes in the preoptic area and rostral hypothalamus on the regulation of food and water intake. Acta Physiol. Scand. 52:175–89
    [Google Scholar]
  82. 82. 
    Yu S, Qualls-Creekmore E, Rezai-Zadeh K, Jiang Y, Berthoud HR et al. 2016. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. J. Neurosci. 36:185034–46
    [Google Scholar]
  83. 83. 
    Nakamura K, Morrison SF. 2008. Preoptic mechanism for cold-defensive responses to skin cooling. J. Physiol. 586:102611–20
    [Google Scholar]
  84. 84. 
    Conceição EPS, Madden CJ, Morrison SF 2019. Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis. Acta Physiol 225:4e13213
    [Google Scholar]
  85. 85. 
    Brito NA, Brito MN, Bartness TJ 2008. Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294:5R1445–52
    [Google Scholar]
  86. 86. 
    Abildgaard J, Henstridge DC, Pedersen AT, Langley KG, Scheele C et al. 2014. In vitro palmitate treatment of myotubes from postmenopausal women leads to ceramide accumulation, inflammation and affected insulin signaling. PLOS ONE 9:7e101555
    [Google Scholar]
  87. 87. 
    Din MU, Saari T, Raiko J, Kudomi N, Maurer SF et al. 2018. Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab 28:220716
    [Google Scholar]
  88. 88. 
    Cheng CYY, Chu JYS, Chow BKC 2011. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 36:2459–71
    [Google Scholar]
  89. 89. 
    Chu JYS, Cheng CYY, Sekar R, Chow BKC 2013. Vagal afferent mediates the anorectic effect of peripheral secretin. PLOS ONE 8:5e64859
    [Google Scholar]
  90. 90. 
    Egawa M, Yoshimatsu H, Bray GA 1991. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 260:2R328–34
    [Google Scholar]
  91. 91. 
    Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD et al. 2014. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159:2306–17
    [Google Scholar]
  92. 92. 
    Shi YC, Lau J, Lin Z, Zhang H, Zhai L et al. 2013. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 17:2236–48
    [Google Scholar]
  93. 93. 
    Ilnytska O, Argyropoulos G. 2008. The role of the Agouti-Related Protein in energy balance regulation. Cell. Mol. Life Sci. 65:172721–31
    [Google Scholar]
  94. 94. 
    Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F et al. 2015. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160:1–288–104
    [Google Scholar]
  95. 95. 
    Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA et al. 2010. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12:178–87
    [Google Scholar]
  96. 96. 
    Voss-Andreae A, Murphy JG, Ellacott KLJ, Stuart RC, Nillni EA et al. 2007. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 148:41550–60
    [Google Scholar]
  97. 97. 
    Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK 2003. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457:3213–35
    [Google Scholar]
  98. 98. 
    Marie LS, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD 2000. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. PNAS 97:2212339–44
    [Google Scholar]
  99. 99. 
    Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q et al. 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:1131–41
    [Google Scholar]
  100. 100. 
    Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H et al. 2005. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123:3493–505
    [Google Scholar]
  101. 101. 
    Rossi J, Balthasar N, Olson D, Scott M, Berglund E et al. 2011. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab 13:2195–204
    [Google Scholar]
  102. 102. 
    Zoeller RT, Tan SW, Tyl RW 2007. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit. Rev. Toxicol. 37:1–211–53
    [Google Scholar]
  103. 103. 
    Ribeiro MO, Lebrun FLAS, Christoffolete MA, Branco M, Crescenzi A et al. 2000. Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat. Am. J. Physiol. Endocrinol. Metab. 279:E314–22
    [Google Scholar]
  104. 104. 
    Cioffi F, Gentile A, Silvestri E, Goglia F, Lombardi A 2018. Effect of iodothyronines on thermogenesis: focus on brown adipose tissue. Front. Endocrinol. 9:254
    [Google Scholar]
  105. 105. 
    van den Berg R, Kooijman S, Noordam R, Ramkisoensing A, Abreu-Vieira G et al. 2018. A diurnal rhythm in brown adipose tissue causes rapid clearance and combustion of plasma lipids at wakening. Cell Rep 22:133521–33
    [Google Scholar]
  106. 106. 
    Hofland J, Bakker J, Feelders RA 2015. What's new on the HPA axis. Intensive Care Med 41:81477–79
    [Google Scholar]
  107. 107. 
    Ramage LE, Akyol M, Fletcher AM, Forsythe J, Nixon M et al. 2016. Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab 24:1130–41
    [Google Scholar]
  108. 108. 
    Thuzar M, Law WP, Ratnasingam J, Jang C, Dimeski G, Ho KKY 2018. Glucocorticoids suppress brown adipose tissue function in humans: a double-blind placebo-controlled study. Diabetes Obes. Metab. 20:4840–48
    [Google Scholar]
  109. 109. 
    Altirriba J, Poher A-L, Rohner-Jeanrenaud F 2015. Chronic oxytocin administration as a treatment against impaired leptin signaling or leptin resistance in obesity. Front. Endocrinol. 6:119
    [Google Scholar]
  110. 110. 
    Kasahara Y, Takayanagi Y, Kawada T, Itoi K, Nishimori K 2007. Impaired thermoregulatory ability of oxytocin-deficient mice during cold-exposure. Biosci. Biotechnol. Biochem. 71:123122–26
    [Google Scholar]
  111. 111. 
    Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, Nishimori K 2008. Oxytocin receptor-deficient mice developed late-onset obesity. Neuroreport 19:9951–55
    [Google Scholar]
  112. 112. 
    Perkins MN, Rothwell NJ, Stock MJ, Stone TW 1981. Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature 289:5796401–2
    [Google Scholar]
  113. 113. 
    Sudo M, Minokoshi Y, Shimazu T 1991. Ventromedial hypothalamic stimulation enhances peripheral glucose uptake in anesthetized rats. Am. J. Physiol. Endocrinol. Metab. 261:3E298–303
    [Google Scholar]
  114. 114. 
    Kim KW, Zhao L, Donato J, Kohno D, Xu Y et al. 2011. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. PNAS 108:2610673–78
    [Google Scholar]
  115. 115. 
    Coutinho EA, Okamoto S, Ishikawa AW, Yokota S, Wada N et al. 2017. Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues. Diabetes 66:92372–86
    [Google Scholar]
  116. 116. 
    Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA et al. 2006. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49:2191–203
    [Google Scholar]
  117. 117. 
    Wang CF, Bomberg E, Billington CJ, Levine AS, Kotz CM 2010. Brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus increases energy expenditure. Brain Res 1336:66–77
    [Google Scholar]
  118. 118. 
    Stuber GD, Wise RA. 2016. Lateral hypothalamic circuits for feeding and reward. Nat. Neurosci. 19:2198–205
    [Google Scholar]
  119. 119. 
    Yamashita T, Yamanaka A. 2017. Lateral hypothalamic circuits for sleep-wake control. Curr. Opin. Neurobiol. 44:94–100
    [Google Scholar]
  120. 120. 
    Bonnavion P, Mickelsen LE, Fujita A, de Lecea L, Jackson AC 2016. Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour. J. Physiol. 594:226443–62
    [Google Scholar]
  121. 121. 
    Cerri M, Morrison SF. 2005. Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience 135:2627–38
    [Google Scholar]
  122. 122. 
    Tupone D, Madden CJ, Cano G, Morrison SF 2011. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J. Neurosci. 31:4415944–55
    [Google Scholar]
  123. 123. 
    Sellayah D, Bharaj P, Sikder D 2011. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 14:4478–90
    [Google Scholar]
  124. 124. 
    Sellayah D, Sikder D. 2014. Orexin restores aging-related brown adipose tissue dysfunction in male mice. Endocrinology 155:2485–501
    [Google Scholar]
  125. 125. 
    Seoane-Collazo P, Liñares-Pose L, Rial-Pensado E, Romero-Picó A, Moreno-Navarrete JM et al. 2019. Central nicotine induces browning through hypothalamic κ opioid receptor. Nat. Commun. 10:4037
    [Google Scholar]
  126. 126. 
    Kataoka N, Hioki H, Kaneko T, Nakamura K 2014. Psychological stress activates a dorsomedial hypothalamus-medullary raphe circuit driving brown adipose tissue thermogenesis and hyperthermia. Cell Metab 20:2346–58
    [Google Scholar]
  127. 127. 
    Yang L, Scott KA, Hyun J, Tamashiro KL, Tray N et al. 2009. Role of dorsomedial hypothalamic neuropeptide Y in modulating food intake and energy balance. J. Neurosci. 29:1179–90
    [Google Scholar]
  128. 128. 
    Chao PT, Yang L, Aja S, Moran TH, Bi S 2011. Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab 13:5573–83
    [Google Scholar]
  129. 129. 
    Lee SJ, Sanchez-Watts G, Krieger JP, Pignalosa A, Norell PN et al. 2018. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity. Mol. Metab. 11:33–46
    [Google Scholar]
  130. 130. 
    Zhang Y, Kerman IA, Laque A, Nguyen P, Faouzi M et al. 2011. Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J. Neurosci. 31:51873–84
    [Google Scholar]
  131. 131. 
    Rezai-Zadeh K, Yu S, Jiang Y, Laque A, Schwartzenburg C et al. 2014. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol. Metab. 3:7681–93
    [Google Scholar]
  132. 132. 
    Enriori PJ, Sinnayah P, Simonds SE, Rudaz CG, Cowley MA 2011. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J. Neurosci. 31:3412189–97
    [Google Scholar]
  133. 133. 
    Zhao S, Zhu Y, Schultz RD, Li N, He Z et al. 2019. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab 30:4706–719.e6
    [Google Scholar]
  134. 134. 
    Neufeld EV, Carney JJ, Dolezal BA, Boland DM, Cooper CB 2017. Exploratory study of heart rate variability and sleep among emergency medical services shift workers. Prehospital Emerg. Care. 21:118–23
    [Google Scholar]
  135. 135. 
    Tobaldini E, Costantino G, Solbiati M, Cogliati C, Kara T et al. 2017. Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. Neurosci. Biobehav. Rev. 74:Part B321–29
    [Google Scholar]
  136. 136. 
    Masri S, Sassone-Corsi P. 2018. The emerging link between cancer, metabolism, and circadian rhythms. Nat. Med. 24:121795–1803
    [Google Scholar]
  137. 137. 
    Walker WH, Walton JC, DeVries AC, Nelson RJ 2020. Circadian rhythm disruption and mental health. Transl. Psychiatry 10:28
    [Google Scholar]
  138. 138. 
    Walker WH, Borniger JC, Gaudier-Diaz MM, Meléndez-Fernández OH, Pascoe JL et al. 2019. Acute exposure to low-level light at night is sufficient to induce neurological changes and depressive-like behavior. Mol. Psychiatry 25:1080–93
    [Google Scholar]
  139. 139. 
    Gerhart-Hines Z, Feng D, Emmett MJ, Everett LJ, Loro E et al. 2013. The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503:7476410–13
    [Google Scholar]
  140. 140. 
    Lee P, Bova R, Schofield L, Bryant W, Dieckmann W et al. 2016. Brown adipose tissue exhibits a glucose-responsive thermogenic biorhythm in humans. Cell Metab 23:4602–9
    [Google Scholar]
  141. 141. 
    Mochizuki T, Klerman EB, Sakurai T, Scammell TE 2006. Elevated body temperature during sleep in orexin knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291:3R533–40
    [Google Scholar]
  142. 142. 
    Vercruysse P, Vieau D, Blum D, Petersén Å, Dupuis L. 2018. Hypothalamic alterations in neurodegenerative diseases and their relation to abnormal energy metabolism. Front. Mol. Neurosci. 11:2
    [Google Scholar]
  143. 143. 
    Gabery S, Halliday G, Kirik D, Englund E, Petersén Å 2015. Selective loss of oxytocin and vasopressin in the hypothalamus in early Huntington disease: a case study. Neuropathol. Appl. Neurobiol. 41:6843–48
    [Google Scholar]
  144. 144. 
    Gabery S, Georgiou-Karistianis N, Lundh SH, Cheong RY, Churchyard A et al. 2015. Volumetric analysis of the hypothalamus in Huntington disease using 3T MRI: The IMAGE-HD study. PLOS ONE 10:2e0117593
    [Google Scholar]
  145. 145. 
    Gorges M, Vercruysse P, Müller HP, Huppertz HJ, Rosenbohm A et al. 2017. Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 88:121033–41
    [Google Scholar]
  146. 146. 
    Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FWC et al. 2012. Hypocretin (orexin) loss in Alzheimer's disease. Neurobiol. Aging 33:81642–50
    [Google Scholar]
  147. 147. 
    Ahmed RM, Latheef S, Bartley L, Irish M, Halliday GM et al. 2015. Eating behavior in frontotemporal dementia. Neurology 85:151310–17
    [Google Scholar]
  148. 148. 
    Bocchetta M, Gordon E, Manning E, Barnes J, Cash DM et al. 2015. Detailed volumetric analysis of the hypothalamus in behavioral variant frontotemporal dementia. J. Neurol. 262:122635–42
    [Google Scholar]
  149. 149. 
    Piguet O, Petersén Å, Yin Ka Lam B, Gabery S, Murphy K et al. 2011. Eating and hypothalamus changes in behavioral-variant frontotemporal dementia. Ann. Neurol. 69:2312–19
    [Google Scholar]
  150. 150. 
    Kok SW, Overeem S, Visscher TLS, Lammers GJ, Seidell JC et al. 2003. Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity. Obes. Res. 11:91147–54
    [Google Scholar]
  151. 151. 
    Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA 2015. Sleep disorders, obesity, and aging: the role of orexin. Ageing Res. Rev. 20:63–73
    [Google Scholar]
  152. 152. 
    Hara J, Yanagisawa M, Sakurai T 2005. Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci. Lett. 380:3239–42
    [Google Scholar]
  153. 153. 
    Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM et al. 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:2345–54
    [Google Scholar]
  154. 154. 
    Sellayah D, Sikder D. 2013. Feeding the heat on brown fat. Ann. N. Y. Acad. Sci. 1302:111–23
    [Google Scholar]
  155. 155. 
    Fronczek R, Overeem S, Reijntjes R, Lammers GJ, van Dijk JG, Pijl H 2008. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy. J. Clin. Sleep Med. 4:3248–54
    [Google Scholar]
  156. 156. 
    Dahmen N, Tonn P, Messroghli L, Ghezel-Ahmadi D, Engel A 2009. Basal metabolic rate in narcoleptic patients. Sleep 32:7962–64
    [Google Scholar]
  157. 157. 
    Enevoldsen LH, Tindborg M, Hovmand NL, Christoffersen C, Ellingsgaard H et al. 2018. Functional brown adipose tissue and sympathetic activity after cold exposure in humans with type 1 narcolepsy. Sleep 41:8zsy092
    [Google Scholar]
  158. 158. 
    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C et al. 2015. Huntington disease. Nat. Rev. Dis. Primers 1:15005
    [Google Scholar]
  159. 159. 
    Cheong RY, Gabery S, Petersén Å 2019. The role of hypothalamic pathology for non-motor features of Huntington's disease. J. Huntington's Dis. 8:4375–91
    [Google Scholar]
  160. 160. 
    Aziz NA, van der Burg JMM, Landwehrmeyer GB, Brundin P, Stijnen T, Roos RAC 2008. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 71:191506–13
    [Google Scholar]
  161. 161. 
    Marder K, Zhao H, Eberly S, Tanner CM, Oakes D, Shoulson I 2009. Dietary intake in adults at risk for Huntington disease: analysis of PHAROS research participants. Neurology 73:5385–92
    [Google Scholar]
  162. 162. 
    Goodman AOG, Murgatroyd PR, Medina-Gomez G, Wood NI, Finer N et al. 2008. The metabolic profile of early Huntington's disease—a combined human and transgenic mouse study. Exp. Neurol. 210:2691–98
    [Google Scholar]
  163. 163. 
    Aziz NA, Pijl H, Frölich M, Snel M, Streefland TCM et al. 2010. Systemic energy homeostasis in Huntington's disease patients. J. Neurol. Neurosurg. Psychiatry 81:111233–37
    [Google Scholar]
  164. 164. 
    van der Burg JMM, Bacos K, Wood NI, Lindqvist A, Wierup N et al. 2008. Increased metabolism in the R6/2 mouse model of Huntington's disease. Neurobiol. Dis. 29:141–51
    [Google Scholar]
  165. 165. 
    Pratley RE, Salbe AD, Ravussin E, Caviness JN 2000. Higher sedentary energy expenditure in patients with Huntington's disease. Ann. Neurol. 47:164–70
    [Google Scholar]
  166. 166. 
    Phan J, Hickey MA, Zhang P, Chesselet M-F, Reue K Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models. Hum. Mol. Genet. 18:61006–16
    [Google Scholar]
  167. 167. 
    Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF et al. 2006. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration. Cell Metab 4:5349–62
    [Google Scholar]
  168. 168. 
    Andreassen OA, Dedeoglu A, Stanojevic V, Hughes DB, Browne SE et al. 2002. Huntington's disease of the endocrine pancreas: Insulin deficiency and diabetes mellitus due to impaired insulin gene expression. Neurobiol. Dis. 11:3410–24
    [Google Scholar]
  169. 169. 
    Chaturvedi RK, Calingasan NY, Yang L, Hennessey T, Johri A, Flint Beal M Impairment of PGC-1α expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington's disease following chronic energy deprivation. Hum. Mol. Genet. 19:163190–3205
    [Google Scholar]
  170. 170. 
    McCourt AC, Jakobsson L, Larsson S, Holm C, Piel S et al. 2016. White adipose tissue browning in the R6/2 mouse model of Huntington's disease. PLOS ONE 11:8e0159870
    [Google Scholar]
  171. 171. 
    Lindenberg KS, Weydt P, Müller HP, Bornstedt A, Ludolph AC et al. 2014. Two-point magnitude MRI for rapid mapping of brown adipose tissue and its application to the R6/2 mouse model of Huntington disease. PLOS ONE 9:8e105556
    [Google Scholar]
  172. 172. 
    Hult S, Soylu R, Björklund T, Belgardt BF, Mauer J et al. 2011. Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits. Cell Metab 13:4428–39
    [Google Scholar]
  173. 173. 
    Van Raamsdonk JM, Gibson WT, Pearson J, Murphy Z, Lu G et al. Body weight is modulated by levels of full-length Huntingtin. Hum. Mol. Genet. 15:91513–23
    [Google Scholar]
  174. 174. 
    Soylu-Kucharz R, Adlesic N, Baldo B, Kirik D, Petersén Å 2015. Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue. Sci. Rep. 5:14598
    [Google Scholar]
  175. 175. 
    van der Burg JMM, Gardiner SL, Ludolph AC, Landwehrmeyer GB, Roos RAC, Aziz NA 2017. Body weight is a robust predictor of clinical progression in Huntington disease. Ann. Neurol. 82:3479–83
    [Google Scholar]
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