Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Leptin and brain–adipose crosstalks

Nature Reviews Neuroscience volume 19, pages 153–165 (2018)Cite this article

Subjects

Key Points

  • Leptin plays a key role in the neural regulation of adipose tissues

  • The sympathetic nervous system is crucial in regulating leptin production

  • Fasting differentially modulates the sympathetic outflow to different fat pads

  • The pattern of sympathetic innervation varies across fat pads and animal species

  • Manipulating the sympathetic outflow to adipose tissues may be beneficial to the development of novel anti-obesity and anti-diabetes therapies

Abstract

Interactions between the brain and distinct adipose depots have a key role in maintaining energy balance, thereby promoting survival in response to metabolic challenges such as cold exposure and starvation. Recently, there has been renewed interest in the specific central neuronal circuits that regulate adipose depots. Here, we review anatomical, genetic and pharmacological studies on the neural regulation of adipose function, including lipolysis, non-shivering thermogenesis, browning and leptin secretion. In particular, we emphasize the role of leptin-sensitive neurons and the sympathetic nervous system in modulating the activity of brown, white and beige adipose tissues. We provide an overview of advances in the understanding of the heterogeneity of the brain regulation of adipose tissues and offer a perspective on the challenges and paradoxes that the community is facing regarding the actions of leptin on this system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sympathetic regulation of white, brown and beige adipose tissues.
Figure 2: Sympathetic regulation of leptin production.
Figure 3: Leptin-sensitive neurons regulating adipose depots.
Figure 4: Sympathetic and sensory innervation of adipose tissues.

Similar content being viewed by others

References

  1. Friedman, J. The long road to leptin. J. Clin. Invest. 126, 4727–4734 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Friedman, J. 20 years of leptin: leptin at 20: an overview. J. Endocrinol. 223, T1–T8 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). This study reports the cloning and sequencing of the mouse Lep gene and has ushered in the molecular era of obesity research.

    CAS  PubMed  Google Scholar 

  4. Ogden, C. L., Carroll, M. D., Fryar, C. D. & Flegal, K. M. Prevalence of obesity among adults and youth: United States, 2011–2014 (US Department of Health and Human Services, 2015).

    Google Scholar 

  5. Chechi, K., Carpentier, A. C. & Richard, D. Understanding the brown adipocyte as a contributor to energy homeostasis. Trends Endocrinol. Metab. 24, 408–420 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Bartness, T. J., Liu, Y., Shrestha, Y. B. & Ryu, V. Neural innervation of white adipose tissue and the control of lipolysis. Front. Neuroendocrinol. 35, 473–493 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Labbe, S. M. et al. Hypothalamic control of brown adipose tissue thermogenesis. Front. Syst. Neurosci. 9, 150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brito, N. A., Brito, M. N. & Bartness, T. J. Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1445–R1452 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Labbe, S. M. et al. Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice. Am. J. Physiol. Endocrinol. Metab. 311, E260–E268 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Morrison, S. F. & Nakamura, K. Central neural pathways for thermoregulation. Front. Biosci. 16, 74–104 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  13. Fishman, R. B. & Dark, J. Sensory innervation of white adipose tissue. Am. J. Physiol. 253, R942–R944 (1987).

    CAS  PubMed  Google Scholar 

  14. Ahima, R. S. & Flier, J. S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Flier, J. S. Clinical review 94: what's in a name? In search of leptin's physiologic role. J. Clin. Endocrinol. Metab. 83, 1407–1413 (1998).

    CAS  PubMed  Google Scholar 

  16. Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Munzberg, H., Qualls-Creekmore, E., Berthoud, H. R., Morrison, C. D. & Yu, S. Neural control of energy expenditure. Handb. Exp. Pharmacol. 233, 173–194 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). This study demonstrates the presence of functional BAT in humans and has contributed to the recent renewed interest in the role of BAT in regulating energy balance.

    Article  CAS  PubMed  Google Scholar 

  21. Caron, A. & Richard, D. Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis. Ann. NY Acad. Sci. 1391, 35–53 (2017).

    Article  PubMed  Google Scholar 

  22. Contreras, C. et al. The brain and brown fat. Ann. Med. 47, 150–168 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Morrison, S. F. & Madden, C. J. Central nervous system regulation of brown adipose tissue. Compr. Physiol. 4, 1677–1713 (2014). This review summarizes the functional organization and neurochemical influences governing BAT sympathetic nerve activity.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Allison, M. B. & Myers, M. G. Jr. 20 years of leptin: connecting leptin signaling to biological function. J. Endocrinol. 223, T25–35 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, H., Matheny, M. & Scarpace, P. J. β3-adrenergic-mediated suppression of leptin gene expression in rats. Am. J. Physiol. 272, E1031–E1036 (1997).

    CAS  PubMed  Google Scholar 

  26. Trayhurn, P., Duncan, J. S. & Rayner, D. V. Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system. Biochem. J. 311, 729–733 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Trayhurn, P., Duncan, J. S., Rayner, D. V. & Hardie, L. J. Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the β3-adrenoceptor agonists BRL 35135A and ZD2079. Biochem. Biophys. Res. Commun. 228, 605–610 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Gettys, T. W., Harkness, P. J. & Watson, P. M. The beta 3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 137, 4054–4057 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Mantzoros, C. S. et al. Activation of β3 adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 45, 909–914 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Furness, J. B. The organisation of the autonomic nervous system: peripheral connections. Auton. Neurosci. 130, 1–5 (2006).

    Article  PubMed  Google Scholar 

  31. McCorry, L. K. Physiology of the autonomic nervous system. Am. J. Pharm. Educ. 71, 78 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kreier, F. et al. Selective parasympathetic innervation of subcutaneous and intra-abdominal fat–functional implications. J. Clin. Invest. 110, 1243–1250 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Giordano, A. et al. White adipose tissue lacks significant vagal innervation and immunohistochemical evidence of parasympathetic innervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1243–R1255 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Jiang, H., Ding, X., Cao, Y., Wang, H. & Zeng, W. Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell Metab. 26, 686–692.e3 (2017). This study reveals a dense network of sympathetic fibres in close apposition with adipocytes. It provides evidence that catecholamines deriving from these sympathetic fibres, but not from the adrenal medulla or resident macrophages, are essential for the development of BeAT.

    Article  CAS  PubMed  Google Scholar 

  35. Gilgen, A., Maickel, R. P., Nikodijevic, O. & Brodie, B. B. Essential role of catecholamines in the mobilization of free fatty acids and glucose after exposure to cold. Life Sci. 1, 709–715 (1962).

    Article  CAS  Google Scholar 

  36. Young, J. B. & Landsberg, L. Suppression of sympathetic nervous system during fasting. Science 196, 1473–1475 (1977).

    Article  CAS  PubMed  Google Scholar 

  37. Migliorini, R. H., Garofalo, M. A. & Kettelhut, I. C. Increased sympathetic activity in rat white adipose tissue during prolonged fasting. Am. J. Physiol. 272, R656–R661 (1997).

    CAS  PubMed  Google Scholar 

  38. Garofalo, M. A., Kettelhut, I. C., Roselino, J. E. & Migliorini, R. H. Effect of acute cold exposure on norepinephrine turnover rates in rat white adipose tissue. J. Auton. Nerv. Syst. 60, 206–208 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Trayhurn, P., Thomas, M. E., Duncan, J. S. & Rayner, D. V. Effects of fasting and refeeding on ob gene expression in white adipose tissue of lean and obese (ob/ob) mice. FEBS Lett. 368, 488–490 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Hube, F. et al. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm. Metab. Res. 28, 690–693 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Koopmans, S. J., Frolich, M., Gribnau, E. H., Westendorp, R. G. & DeFronzo, R. A. Effect of hyperinsulinemia on plasma leptin concentrations and food intake in rats. Am. J. Physiol. 274, E998–E1001 (1998).

    CAS  PubMed  Google Scholar 

  44. Sukumaran, S., Xue, B., Jusko, W. J., Dubois, D. C. & Almon, R. R. Circadian variations in gene expression in rat abdominal adipose tissue and relationship to physiology. Physiol. Genomics 42A, 141–152 (2010).

  45. Boden, G., Chen, X., Mozzoli, M. & Ryan, I. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab. 81, 3419–3423 (1996).

    CAS  PubMed  Google Scholar 

  46. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Murakami, T., Iida, M. & Shima, K. Dexamethasone regulates obese expression in isolated rat adipocytes. Biochem. Biophys. Res. Commun. 214, 1260–1267 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Saladin, R. et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 377, 527–529 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Moinat, M. et al. Modulation of obese gene expression in rat brown and white adipose tissues. FEBS Lett. 373, 131–134 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Deng, C. et al. Effects of β-adrenoceptor subtype stimulation on obese gene messenger ribonucleic acid and on leptin secretion in mouse brown adipocytes differentiated in culture. Endocrinology 138, 548–552 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Trayhurn, P., Duncan, J. S., Hoggard, N. & Rayner, D. V. Regulation of leptin production: a dominant role for the sympathetic nervous system? Proc. Nutr. Soc. 57, 413–419 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Giacobino, J. P. Role of the β3-adrenoceptor in the control of leptin expression. Horm. Metab. Res. 28, 633–637 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Slieker, L. J. et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J. Biol. Chem. 271, 5301–5304 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Rayner, D. V., Simon, E., Duncan, J. S. & Trayhurn, P. Hyperleptinaemia in mice induced by administration of the tyrosine hydroxylase inhibitor α-methyl-p-tyrosine. FEBS Lett. 429, 395–398 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Sivitz, W. I. et al. Sympathetic inhibition, leptin, and uncoupling protein subtype expression in normal fasting rats. Am. J. Physiol. 277, E668–E677 (1999).

    CAS  PubMed  Google Scholar 

  56. Tieu, K. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb. Perspect. Med. 1, a009316 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang, T. S., Wang, Y. H. & Chen, S. Y. The relation of serum leptin to body mass index and to serum cortisol in men with spinal cord injury. Arch. Phys. Med. Rehabil. 81, 1582–1586 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Commins, S. P. et al. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 140, 4772–4778 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Pereira, M. M. et al. A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nat. Commun. 8, 14967 (2017). This study reports the development of a novel tool allowing chemical genetic ablation of genes of interest strictly in peripheral tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bartolomucci, A. et al. TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity. Proc. Natl Acad. Sci. USA 103, 14584–14589 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Cero, C. et al. The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis. Mol. Metab. 6, 148–158 (2017).

    Article  CAS  PubMed  Google Scholar 

  62. Fuke, T. et al. Transcription factor AP-2β inhibits expression and secretion of leptin, an insulin-sensitizing hormone, in 3T3-L1 adipocytes. Int. J. Obes. 34, 670–678 (2010).

    Article  CAS  Google Scholar 

  63. Wrann, C. D. et al. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J. Clin. Invest. 122, 1010–1021 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lu, Y. H., Dallner, O. S., Birsoy, K., Fayzikhodjaeva, G. & Friedman, J. M. Nuclear factor-Y is an adipogenic factor that regulates leptin gene expression. Mol. Metab. 4, 392–405 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. de la Brousse, F. C., Shan, B. & Chen, J. L. Identification of the promoter of the mouse obese gene. Proc. Natl Acad. Sci. USA 93, 4096–4101 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. Gong, D. W., Bi, S., Pratley, R. E. & Weintraub, B. D. Genomic structure and promoter analysis of the human obese gene. J. Biol. Chem. 271, 3971–3974 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. He, Y., Chen, H., Quon, M. J. & Reitman, M. The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein α. J. Biol. Chem. 270, 28887–28891 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Hwang, C. S., Mandrup, S., MacDougald, O. A., Geiman, D. E. & Lane, M. D. Transcriptional activation of the mouse obese (ob) gene by CCAAT/enhancer binding protein α. Proc. Natl Acad. Sci. USA 93, 873–877 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Miller, S. G. et al. The adipocyte specific transcription factor C/EBPα modulates human ob gene expression. Proc. Natl Acad. Sci. USA 93, 5507–5511 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Kim, J. B. et al. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J. Clin. Invest. 101, 1–9 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen, X. L., Hartzell, D. L., McGraw, R. A., Hausman, G. J. & Dean, R. G. Analysis of a 762-bp proximal leptin promoter to drive and control regulation of transgene expression of growth hormone receptor in mice. Biochem. Biophys. Res. Commun. 262, 187–192 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Wrann, C. D. & Rosen, E. D. New insights into adipocyte-specific leptin gene expression. Adipocyte 1, 168–172 (2012). This review highlights the transcriptional mechanisms that regulate adipocyte-specific expression of leptin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Becker, D. J., Ongemba, L. N., Brichard, V., Henquin, J. C. & Brichard, S. M. Diet- and diabetes-induced changes of ob gene expression in rat adipose tissue. FEBS Lett. 371, 324–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. MacDougald, O. A., Hwang, C. S., Fan, H. & Lane, M. D. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. Proc. Natl Acad. Sci. USA 92, 9034–9037 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Hardie, L. J., Rayner, D. V., Holmes, S. & Trayhurn, P. Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochem. Biophys. Res. Commun. 223, 660–665 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Szkudelski, T. Intracellular mediators in regulation of leptin secretion from adipocytes. Physiol. Res. 56, 503–512 (2007).

    CAS  PubMed  Google Scholar 

  77. Rayner, D. V. The sympathetic nervous system in white adipose tissue regulation. Proc. Nutr. Soc. 60, 357–364 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Cusin, I., Rohner-Jeanrenaud, F., Stricker-Krongrad, A. & Jeanrenaud, B. The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats: reduced sensitivity compared with lean animals. Diabetes 45, 1446–1450 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Kusminski, C. M., Bickel, P. E. & Scherer, P. E. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat. Rev. Drug Discov. 15, 639–660 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Caron, A., Richard, D. & Laplante, M. The roles of mTOR complexes in lipid metabolism. Annu. Rev. Nutr. 35, 321–348 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nishizawa, Y. & Bray, G. A. Ventromedial hypothalamic lesions and the mobilization of fatty acids. J. Clin. Invest. 61, 714–721 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takahashi, A. & Shimazu, T. Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipolysis. J. Auton. Nerv. Syst. 4, 195–205 (1981).

    Article  CAS  PubMed  Google Scholar 

  85. Youngstrom, T. G. & Bartness, T. J. White adipose tissue sympathetic nervous system denervation increases fat pad mass and fat cell number. Am. J. Physiol. 275, R1488–R1493 (1998).

    CAS  PubMed  Google Scholar 

  86. Bamshad, M., Aoki, V. T., Adkison, M. G., Warren, W. S. & Bartness, T. J. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am. J. Physiol. 275, R291–R299 (1998).

    CAS  PubMed  Google Scholar 

  87. Bartness, T. J. & Bamshad, M. Innervation of mammalian white adipose tissue: implications for the regulation of total body fat. Am. J. Physiol. 275, R1399–R1411 (1998).

    CAS  PubMed  Google Scholar 

  88. Sahu, A. Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. J. Neuroendocrinol. 14, 796–804 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Buettner, C. et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat. Med. 14, 667–675 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shen, J., Tanida, M., Niijima, A. & Nagai, K. In vivo effects of leptin on autonomic nerve activity and lipolysis in rats. Neurosci. Lett. 416, 193–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Rooks, C. R. et al. Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R92–R102 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Penn, D. M., Jordan, L. C., Kelso, E. W., Davenport, J. E. & Harris, R. B. Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1613–R1621 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Jaubert, A. M., Penot, G., Niang, F., Durant, S. & Forest, C. Rapid nitration of adipocyte phosphoenolpyruvate carboxykinase by leptin reduces glyceroneogenesis and induces fatty acid release. PLoS ONE 7, e40650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rodriguez, V. M., Macarulla, M. T., Echevarria, E. & Portillo, M. P. Lipolysis induced by leptin in rat adipose tissue from different anatomical locations. Eur. J. Nutr. 42, 149–153 (2003).

    CAS  PubMed  Google Scholar 

  95. Siegrist-Kaiser, C. A. et al. Direct effects of leptin on brown and white adipose tissue. J. Clin. Invest. 100, 2858–2864 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. D'Souza, A., M., Neumann, U. H., Glavas, M. M. & Kieffer, T. J. The glucoregulatory actions of leptin. Mol. Metab. 6, 1052–1065 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Warner, A. et al. Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats. Am. J. Physiol. Endocrinol. Metab. 311, E901–E910 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Plum, L. et al. Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab. 6, 431–445 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Chi, J. et al. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab. 27, 226–236.e3 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Zhu, Y. et al. Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals. Cell Metab. 24, 420–433 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ruan, H. B. et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159, 306–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. de Jong, J. M., Larsson, O., Cannon, B. & Nedergaard, J. A stringent validation of mouse adipose tissue identity markers. Am. J. Physiol. Endocrinol. Metab. 308, E1085–E1105 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Foster, D. O. Quantitative contribution of brown adipose tissue thermogenesis to overall metabolism. Can. J. Biochem. Cell Biol. 62, 618–622 (1984).

    Article  CAS  PubMed  Google Scholar 

  104. Labbe, S. M. et al. In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis. FASEB J. 29, 2046–2058 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004). This is a comprehensive and detailed review of BAT biology.

    Article  CAS  Google Scholar 

  106. Murano, I., Barbatelli, G., Giordano, A. & Cinti, S. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J. Anat. 214, 171–178 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Bartness, T. J. & Song, C. K. Innervation of brown adipose tissue and its role in thermogenesis. Can. J. Diabetes 29, 420–428 (2005).

    CAS  Google Scholar 

  108. Bamshad, M., Song, C. K. & Bartness, T. J. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. 276, R1569–R1578 (1999).

    CAS  PubMed  Google Scholar 

  109. Nguyen, N. L. et al. 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, R132–R145 (2017). This paper provides neuroanatomical and functional evidence of the existence of SNS crosstalk for thermoregulation and BeAT development.

    Article  PubMed  Google Scholar 

  110. Cano, G. et al. Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J. Comp. Neurol. 460, 303–326 (2003). This study demonstrates the central circuitry responsible for cold-induced increase in sympathetic outflow to interscapular BAT.

    Article  PubMed  Google Scholar 

  111. Morrison, S. F., Ramamurthy, S. & Young, J. B. Reduced rearing temperature augments responses in sympathetic outflow to brown adipose tissue. J. Neurosci. 20, 9264–9271 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Yu, S. et al. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. J. Neurosci. 36, 5034–5046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fischer, A. W. et al. Leptin raises defended body temperature without activating thermogenesis. Cell Rep. 14, 1621–1631 (2016). This recent study suggests that leptin is pyrexic rather than thermogenic.

    Article  CAS  PubMed  Google Scholar 

  114. Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Satoh, N. et al. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48, 1787–1793 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Haque, M. S. et al. Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes 48, 1706–1712 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. De Fanti, B. A., Milagro, F. I., Lamas, O., Martinez-Anso, E. & Martinez, J. A. Immunomanipulation of appetite and body temperature through the functional mimicry of leptin. Obes. Res. 10, 833–837 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Luheshi, G. N., Gardner, J. D., Rushforth, D. A., Loudon, A. S. & Rothwell, N. J. Leptin actions on food intake and body temperature are mediated by IL-1. Proc. Natl Acad. Sci. USA 96, 7047–7052 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Dodd, G. T. et al. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab. 20, 639–649 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Collins, S. et al. Role of leptin in fat regulation. Nature 380, 677 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Morrison, S. F. Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R832–837 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L. & Sivitz, W. I. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100, 270–278 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kamohara, S., Burcelin, R., Halaas, J. L., Friedman, J. M. & Charron, M. J. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389, 374–377 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Harlan, S. M., Guo, D. F., Morgan, D. A., Fernandes-Santos, C. & Rahmouni, K. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 17, 599–606 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rahmouni, K. & Morgan, D. A. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension 49, 647–652 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. do Carmo, J. M. et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57, 918–926 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Scarpace, P. J. & Matheny, M. Leptin induction of UCP1 gene expression is dependent on sympathetic innervation. Am. J. Physiol. 275, E259–E264 (1998).

    CAS  PubMed  Google Scholar 

  129. Haynes, W. G., Sivitz, W. I., Morgan, D. A., Walsh, S. A. & Mark, A. L. Sympathetic and cardiorenal actions of leptin. Hypertension 30, 619–623 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Sarmiento, U. et al. Morphologic and molecular changes induced by recombinant human leptin in the white and brown adipose tissues of C57BL/6 mice. Lab. Invest. 77, 243–256 (1997).

    CAS  PubMed  Google Scholar 

  131. Harris, R. B. et al. A leptin dose-response study in obese (ob/ob) and lean (+/?) mice. Endocrinology 139, 8–19 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Commins, S. P. et al. Induction of uncoupling protein expression in brown and white adipose tissue by leptin. Endocrinology 140, 292–300 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Kaiyala, K. J., Ogimoto, K., Nelson, J. T., Muta, K. & Morton, G. J. Physiological role for leptin in the control of thermal conductance. Mol. Metab. 5, 892–902 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ottaway, N. et al. Diet-induced obese mice retain endogenous leptin action. Cell Metab. 21, 877–882 (2015). This study shows that the anorexigenic effects of leptin are maintained in hyperleptinaemic diet-induced obesity mice through the use of a novel leptin receptor antagonist.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ryu, V. & Bartness, T. J. Short and long sympathetic-sensory feedback loops in white fat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R886–R900 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Shi, H. & Bartness, T. J. Neurochemical phenotype of sympathetic nervous system outflow from brain to white fat. Brain Res. Bull. 54, 375–385 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Song, C. K., Jackson, R. M., Harris, R. B., Richard, D. & Bartness, T. J. Melanocortin-4 receptor mRNA is expressed in sympathetic nervous system outflow neurons to white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1467–R1476 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Song, C. K. et al. 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, R417–R428 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mercer, J. G. et al. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 387, 113–116 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Elmquist, J. K., Bjorbaek, C., Ahima, R. S., Flier, J. S. & Saper, C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547 (1998).

    Article  CAS  PubMed  Google Scholar 

  141. Laque, A. et al. Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action. Am. J. Physiol. Endocrinol. Metab. 304, E999–E1011 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cone, R. D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 8, 571–578 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  144. Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Elias, C. F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21, 1375–1385 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Kishi, T. et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457, 213–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308 (1994).

    CAS  PubMed  Google Scholar 

  148. Begriche, K., Sutton, G. M. & Butler, A. A. Homeostastic and non-homeostatic functions of melanocortin-3 receptors in the control of energy balance and metabolism. Physiol. Behav. 104, 546–554 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  150. Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  151. Begriche, K., Girardet, C., McDonald, P. & Butler, A. A. Melanocortin-3 receptors and metabolic homeostasis. Prog. Mol. Biol. Transl Sci. 114, 109–146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Satoh, N. et al. Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system. Neurosci. Lett. 249, 107–110 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Haynes, W. G., Morgan, D. A., Djalali, A., Sivitz, W. I. & Mark, A. L. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 33, 542–547 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Williams, D. L., Bowers, R. R., Bartness, T. J., Kaplan, J. M. & Grill, H. J. Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Endocrinology 144, 4692–4697 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Voss-Andreae, A. et al. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 148, 1550–1560 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Berglund, E. D. et al. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat. Neurosci. 17, 911–913 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Henry, F. E., Sugino, K., Tozer, A., Branco, T. & Sternson, S. M. Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. eLife 4, e09800 (2015).

    Article  PubMed Central  Google Scholar 

  159. Lam, B. Y. H. et al. Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. Mol. Metab. 6, 383–392 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kong, D. et al. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151, 645–657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Dodd, G. T. et al. A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metab. 26, 375–393.e7 (2017).

    Article  CAS  PubMed  Google Scholar 

  164. Thompson, R. H. & Swanson, L. W. Organization of inputs to the dorsomedial nucleus of the hypothalamus: a reexamination with Fluorogold and PHAL in the rat. Brain Res. Brain Res. Rev. 27, 89–118 (1998).

    Article  CAS  PubMed  Google Scholar 

  165. Yoshida, K. et al. Neurons of the rat preoptic area and the raphe pallidus nucleus innervating the brown adipose tissue express the prostaglandin E receptor subtype EP3. Eur. J. Neurosci. 18, 1848–1860 (2003).

    Article  PubMed  Google Scholar 

  166. Trayhurn, P., Thurlby, P. L. & James, W. P. A defective response to cold in the obese (obob) mouse and the obese Zucker (fafa) rat [proceedings]. Proc. Nutr. Soc. 35, 133A (1976).

    CAS  PubMed  Google Scholar 

  167. Trayhurn, P., Thurlby, P. L. & James, W. P. Thermogenic defect in pre-obese ob/ob mice. Nature 266, 60–62 (1977).

    Article  CAS  PubMed  Google Scholar 

  168. Zhang, Y. et al. Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J. Neurosci. 31, 1873–1884 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Rezai-Zadeh, K. et al. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol. Metab. 3, 681–693 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Steiner, A. A. et al. A new function of the leptin receptor: mediation of the recovery from lipopolysaccharide-induced hypothermia. FASEB J. 18, 1949–1951 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Xu, Y. et al. Glutamate release mediates leptin action on energy expenditure. Mol. Metab. 2, 109–115 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zaretskaia, M. V., Zaretsky, D. V., Shekhar, A. & DiMicco, J. A. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res. 928, 113–125 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Cao, W. H., Fan, W. & Morrison, S. F. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience 126, 229–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Dimicco, J. A. & Zaretsky, D. V. The dorsomedial hypothalamus: a new player in thermoregulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R47–R63 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773–797 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Gautron, L., Lazarus, M., Scott, M. M., Saper, C. B. & Elmquist, J. K. Identifying the efferent projections of leptin-responsive neurons in the dorsomedial hypothalamus using a novel conditional tracing approach. J. Comp. Neurol. 518, 2090–2108 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Elmquist, J. K., Ahima, R. S., Elias, C. F., Flier, J. S. & Saper, C. B. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl Acad. Sci. USA 95, 741–746 (1998).

    Article  CAS  PubMed  Google Scholar 

  178. Elias, C. F. et al. Chemical characterization of leptin-activated neurons in the rat brain. J. Comp. Neurol. 423, 261–281 (2000).

    Article  CAS  PubMed  Google Scholar 

  179. Marsh, A. J. et al. Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension 42, 488–493 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. Enriori, P. J., Sinnayah, P., Simonds, S. E., Garcia Rudaz, C. & Cowley, M. A. Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J. Neurosci. 31, 12189–12197 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Iijima, N. et al. Cytochemical study of prolactin-releasing peptide (PrRP) in the rat brain. Neuroreport 10, 1713–1716 (1999).

    Article  CAS  PubMed  Google Scholar 

  182. Lam, D. D. et al. Leptin does not directly affect CNS serotonin neurons to influence appetite. Cell Metab. 13, 584–591 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yoshida, T. & Bray, G. A. Catecholamine turnover in rats with ventromedial hypothalamic lesions. Am. J. Physiol. 246, R558–R565 (1984).

    Article  CAS  PubMed  Google Scholar 

  184. Saito, M., Minokoshi, Y. & Shimazu, T. Ventromedial hypothalamic stimulation accelerates norepinephrine turnover in brown adipose tissue of rats. Life Sci. 41, 193–197 (1987).

    Article  CAS  PubMed  Google Scholar 

  185. Perkins, M. N., Rothwell, N. J., Stock, M. J. & Stone, T. W. Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature 289, 401–402 (1981).

    Article  CAS  PubMed  Google Scholar 

  186. Holt, S. J., Wheal, H. V. & York, D. A. Hypothalamic control of brown adipose tissue in Zucker lean and obese rats. Effect of electrical stimulation of the ventromedial nucleus and other hypothalamic centres. Brain Res. 405, 227–233 (1987).

    Article  CAS  PubMed  Google Scholar 

  187. Hugie, T., Halvorson, I. & Thornhill, J. Brown adipose tissue temperature responses following electrical stimulation of ventromedial hypothalamic and lateral preoptic areas or after norepinephrine infusion to Long Evans or Sprague-Dawley rats. Brain Res. 575, 57–62 (1992).

    Article  CAS  PubMed  Google Scholar 

  188. Ruffin, M. & Nicolaidis, S. Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior. Brain Res. 846, 23–29 (1999).

    Article  CAS  PubMed  Google Scholar 

  189. Minokoshi, Y., Haque, M. S. & Shimazu, T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 48, 287–291 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Toda, C. et al. Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues. Diabetes 58, 2757–2765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ikeda, Y., Luo, X., Abbud, R., Nilson, J. H. & Parker, K. L. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol. Endocrinol. 9, 478–486 (1995).

    CAS  PubMed  Google Scholar 

  192. Bingham, N. C., Anderson, K. K., Reuter, A. L., Stallings, N. R. & Parker, K. L. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149, 2138–2148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. Kim, K. W. et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc. Natl Acad. Sci. USA 108, 10673–10678 (2011).

    Article  PubMed  Google Scholar 

  195. Hill, C. E., Gould, D. J., Strigas, J., Burcher, E. & Vidovic, M. Sensory nerves play an efferent role in the function of the arterioles, but not the dilator muscle, of the rat iris. J. Auton. Nerv. Syst. 58, 89–100 (1996).

    Article  CAS  PubMed  Google Scholar 

  196. Norman, D., Mukherjee, S., Symons, D., Jung, R. T. & Lever, J. D. Neuropeptides in interscapular and perirenal brown adipose tissue in the rat: a plurality of innervation. J. Neurocytol. 17, 305–311 (1988).

    Article  CAS  PubMed  Google Scholar 

  197. De Matteis, R., Ricquier, D. & Cinti, S. TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study. J. Neurocytol. 27, 877–886 (1998).

    Article  CAS  PubMed  Google Scholar 

  198. Giordano, A., Morroni, M., Santone, G., Marchesi, G. F. & Cinti, S. Tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide and vasoactive intestinal peptide in nerves of rat periovarian adipose tissue: an immunohistochemical and ultrastructural investigation. J. Neurocytol. 25, 125–136 (1996).

    Article  CAS  PubMed  Google Scholar 

  199. Song, C. K., Schwartz, G. J. & Bartness, T. J. Anterograde transneuronal viral tract tracing reveals central sensory circuits from white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R501–R511 (2009).

    Article  CAS  PubMed  Google Scholar 

  200. Niijima, A. Afferent signals from leptin sensors in the white adipose tissue of the epididymis, and their reflex effect in the rat. J. Auton. Nerv. Syst. 73, 19–25 (1998).

    Article  CAS  PubMed  Google Scholar 

  201. Niijima, A. Reflex effects from leptin sensors in the white adipose tissue of the epididymis to the efferent activity of the sympathetic and vagus nerve in the rat. Neurosci. Lett. 262, 125–128 (1999).

    Article  CAS  PubMed  Google Scholar 

  202. Murphy, K. T. et al. Leptin-sensitive sensory nerves innervate white fat. Am. J. Physiol. Endocrinol. Metab. 304, E1338–E1347 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Shi, Z. et al. Sympathetic activation by chemical stimulation of white adipose tissues in rats. J. Appl. Physiol. 112, 1008–1014 (2012).

    Article  CAS  PubMed  Google Scholar 

  204. Lafontan, M. & Berlan, M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J. Lipid Res. 34, 1057–1091 (1993).

    CAS  PubMed  Google Scholar 

  205. Montague, C. T., Prins, J. B., Sanders, L., Digby, J. E. & O'Rahilly, S. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 46, 342–347 (1997).

    Article  CAS  PubMed  Google Scholar 

  206. Tchkonia, T. et al. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 17, 644–656 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Flier, J. S. & Maratos-Flier, E. Leptin's physiologic role: does the emperor of energy balance have no clothes? Cell Metab. 26, 24–26 (2017).

    Article  CAS  PubMed  Google Scholar 

  208. Nguyen, N. L., Randall, J., Banfield, B. W. & Bartness, T. J. Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R375–R386 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Brito, M. N., Brito, N. A., Baro, D. J., Song, C. K. & Bartness, T. J. Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. Endocrinology 148, 5339–5347 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Youngstrom, T. G. & Bartness, T. J. Catecholaminergic innervation of white adipose tissue in Siberian hamsters. Am. J. Physiol. 268, R744–R751 (1995).

    CAS  PubMed  Google Scholar 

  211. Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017). This recent study demonstrates that sympathetic-neuron-associated macrophages can metabolize catecholamines, thus identifying a new molecular target for the treatment of obesity.

    Article  CAS  PubMed  Google Scholar 

  212. Zhang, F. et al. An adipose tissue atlas: an image-guided identification of human-like BAT and beige depots in rodents. Cell Metab. 27, 252–262.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by US National Institutes of Health grants DK053301, R01 DK088423 and R01 DK100659 to J.K.E. A.C. is a Canadian Diabetes Association postdoctoral fellow.

Author information

Authors and Affiliations

  1. Division of Hypothalamic Research and Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Alexandre Caron, Syann Lee, Joel K. Elmquist & Laurent Gautron

Authors
  1. Alexandre Caron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syann Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joel K. Elmquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurent Gautron
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.C. wrote the manuscript and prepared the figures. J.K.E., A.C., L.G. and S.L. researched, discussed and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Joel K. Elmquist or Laurent Gautron.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

SNS outflow

The release of neurotransmitters derived from sympathetic neurons in peripheral tissues.

Fat mobilization

A process, in response to signals for energy, in which fatty acids are released from triglyceride stores in fat cells and delivered to organs.

Dermomyotome

The epithelial cell layer constituting the dorsal part of the somite lying under the ectoderm. It gives rise to the dorsal dermis and to the skeletal muscle of the myotome.

Bilateral chain

A symmetric chain of sympathetic ganglia located just ventral and lateral to the spinal cord.

Terminal ganglia

Parasympathetic ganglia situated within or close to an innervated organ and the site where preganglionic nerve fibres terminate.

Noradrenaline turnover

A surrogate index of changes in sympathetic activation, based on the assumption that tissue levels of noradrenaline decline at a rate proportional to initial noradrenaline concentrations. Increased noradrenaline turnover implies increased sympathetic activation.

Zeitgeber time

A quantification of time based on the period of a zeitgeber. Under standard light–dark cycles, the time at lights-on is usually defined as zeitgeber time 0 for diurnal organisms, and the time at lights-off is defined as zeitgeber time 12 for nocturnal animals.

β-Blockers

β-Adrenergic blocking agents that prevent the effects of the hormone adrenaline.

Ectopic lipid accumulation

An accumulation of lipids in lean tissues such as kidneys, liver, muscle and heart that results in lipotoxicity and metabolic diseases.

Lipotoxicity

The accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death.

Multilocularity

The appearance of cytoplasmic lipids arranged in numerous small droplets.

Thoracolumbar ganglia

Ganglia arising from the thoracolumbar (T1–L2) regions of the spinal cord.

Fluoro-gold

A fluorescent retrograde axonal tracer.

Thermoneutrality

The state of thermal balance at which an organism does not need to generate heat in order to maintain a normal core temperature.

Pyrexic

Relating to factors that raise body temperature above normal.

Leptin resistance

Reduced sensitivity with respect to the metabolic responses to exogenously administered leptin.

Calorimetry

The process of measuring the amount of energy as heat released, or absorbed, by an organism.

O-GlcNAc transferase

(OGT). An enzyme that catalyses the addition of an N-acetylglucosamine group in O-glycosidic linkage to serine or threonine residues of intracellular proteins.

Hypothermic

A condition that leads to a decrease in body core temperature — be that regulated, accidental or forced — when the body dissipates more heat than it generates.

Anapyrexic

Relating to decreases in body temperature below normal.

Lipopolysaccharide

Large molecules found in the outer membrane of Gram-negative bacteria. They elicit strong immune responses.

Omental

Adipose tissue located in the omentum, a layer of peritoneum that surrounds abdominal organs.

Cachexia

A syndrome characterized by uncontrolled weight loss, muscle atrophy, fatigue and weakness.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caron, A., Lee, S., Elmquist, J. et al. Leptin and brain–adipose crosstalks. Nat Rev Neurosci 19, 153–165 (2018). https://doi.org/10.1038/nrn.2018.7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2018.7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing