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.

Obesity: a neuroimmunometabolic perspective

Abstract

Neuroimmunology and immunometabolism are burgeoning topics of study, but the intersection of these two fields is scarcely considered. This interplay is particularly prevalent within adipose tissue, where immune cells and the sympathetic nervous system (SNS) have an important role in metabolic homeostasis and pathology, namely in obesity. In the present Review, we first outline the established reciprocal adipose–SNS relationship comprising the neuroendocrine loop facilitated primarily by adipose tissue-derived leptin and SNS-derived noradrenaline. Next, we review the extensive crosstalk between adipocytes and resident innate immune cells as well as the changes that occur in these secretory and signalling pathways in obesity. Finally, we discuss the effect of SNS adrenergic signalling in immune cells and conclude with exciting new research demonstrating an immutable role for SNS-resident macrophages in modulating SNS–adipose crosstalk. We posit that the latter point constitutes the existence of a new field — neuroimmunometabolism.

Key points

  • Adipose tissue is innervated by sympathetic nerves that release noradrenaline, which drives thermogenesis in brown adipose tissue and lipolysis and/or beiging in white adipose tissue.

  • Adipocytes release leptin and other adipokines that signal through the hypothalamus to control whole-body metabolism, including modulation of sympathetic output to adipose tissue.

  • The polarization of adipose-resident macrophages is a prominent effector in obesity and insulin resistance. This polarization is sensitive to signalling from other immune cells, adipocytes and sympathetic nerves.

  • Adipokines, such as leptin and adiponectin, directly modulate the activation status of macrophages and other immune cells. Adipokine release changes drastically in obesity.

  • Noradrenaline released by sympathetic nerves directly modulates macrophages and other immune cells by signalling through various subtypes of adrenoreceptor.

  • Small populations of macrophages have been discovered by several groups in various adipose depots that closely associate with sympathetic nerves and play a novel role in modulating sympathetic innervation of adipose tissue.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: Neuroimmunometabolic triad.
Fig. 2: Hypothalamic–SNS fat loop.
Fig. 3: Adipose–immune communication.
Fig. 4: Sympathetic neuron-associated macrophages in adipose tissue.

Similar content being viewed by others

References

  1. Chu, D. T. et al. An update on physical health and economic consequences of overweight and obesity. Diabetes Metab. Syndr. 12, 1095–1100 (2018).

    Article  PubMed  Google Scholar 

  2. Bachman, E. S. et al. βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297, 843–845 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Galton, D. J. & Bray, G. A. Studies on lipolysis in human adipose cells. J. Clin. Invest. 46, 621–629 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goodner, C. J., Tustison, W. A., Davidson, M. B., Chu, P. C. & Conway, M. J. Studies of substrate regulation in fasting. I. Evidence for central regulation of lipolysis by plasma glucose mediated by the sympathetic nervous system. Diabetes 16, 576–589 (1967).

    Article  CAS  PubMed  Google Scholar 

  7. Bogdonoff, M. D., Weissler, A. M. & Merritt, F. L. The effect of autonomic ganglionic blockade upon serum free fatty acid levels in man. J. Clin. Invest. 39, 959–965 (1960).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fredholm, B. & Rosell, S. Effects of adrenergic blocking agents on lipid mobilization from canine subcutaneous adipose tissue after sympathetic nerve stimulation. J. Pharmacol. Exp. Ther. 159, 1–7 (1968).

    CAS  PubMed  Google Scholar 

  9. Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bartness, T. J. & Song, C. K. Brain-adipose tissue neural crosstalk. Physiol. Behav. 91, 343–351 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Bartness, T. J., Shrestha, Y. B., Vaughan, C. H., Schwartz, G. J. & Song, C. K. Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol. Cell Endocrinol. 318, 34–43 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Bowers, R. R. et al. Sympathetic innervation of white adipose tissue and its regulation of fat cell number. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R1167–R1175 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. 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 

  16. Pereira, M. M. et al. A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nat. Commun. 8, 14967 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Blaszkiewicz, M. W. et al. Neuropathy and neural plasticity in the subcutaneous white adipose depot. PLOS ONE 14, e0221766 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Francois, M. et al. Sympathetic innervation of the interscapular brown adipose tissue in mouse. Ann. NY Acad. Sci. 1454, 3–13 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. 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  PubMed Central  Google Scholar 

  22. 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 

  23. Uyama, N., Geerts, A. & Reynaert, H. Neural connections between the hypothalamus and the liver. Anat. Rec. A. Discov. Mol. Cell Evol. Biol. 280, 808–820 (2004).

    Article  PubMed  Google Scholar 

  24. 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 

  25. Young, J. B., Saville, E., Rothwell, N. J., Stock, M. J. & Landsberg, L. Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat. J. Clin. Invest. 69, 1061–1071 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. Guilherme, A., Henriques, F., Bedard, A. H. & Czech, M. P. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat. Rev. Endocrinol. 15, 207–225 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bartness, T. J. & Song, C. K. Thematic review series: adipocyte biology. Sympathetic and sensory innervation of white adipose tissue. J. Lipid Res. 48, 1655–1672 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Bartness, T. J., Vaughan, C. H. & Song, C. K. Sympathetic and sensory innervation of brown adipose tissue. Int. J. Obes. 34, S36–S42 (2010).

    Article  Google Scholar 

  30. Foster, M. T. & Bartness, T. J. Sympathetic but not sensory denervation stimulates white adipocyte proliferation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1630–R1637 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Garretson, J. T. et al. Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol. Metab. 5, 626–634 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Shi, H. & Bartness, T. J. White adipose tissue sensory nerve denervation mimics lipectomy-induced compensatory increases in adiposity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R514–R520 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scott, M. M. et al. Leptin targets in the mouse brain. J. Comp. Neurol. 514, 518–532 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 

  39. Ramseyer, V. D. & Granneman, J. G. Adrenergic regulation of cellular plasticity in brown, beige/brite and white adipose tissues. Adipocyte 5, 119–129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Coppari, R. & Bjorbaek, C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat. Rev. Drug Discov. 11, 692–708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caron, A., Lee, S., Elmquist, J. K. & Gautron, L. Leptin and brain-adipose crosstalks. Nat. Rev. Neurosci. 19, 153–165 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. 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 

  44. Bell, B. B., Harlan, S. M., Morgan, D. A., Guo, D. F. & Rahmouni, K. Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin. Mol. Metab. 8, 1–12 (2018).

    Article  PubMed  CAS  Google Scholar 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. Roelfsema, F., Boelen, A., Kalsbeek, A. & Fliers, E. Regulatory aspects of the human hypothalamus-pituitary-thyroid axis. Best Pract. Res. Clin. Endocrinol. Metab. 31, 487–503 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Lopez, M., Alvarez, C. V., Nogueiras, R. & Dieguez, C. Energy balance regulation by thyroid hormones at central level. Trends Mol. Med. 19, 418–427 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Alvarez-Crespo, M. et al. Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance. Mol. Metab. 5, 271–282 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Martinez-Sanchez, N. et al. Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance. Cell Metab. 26, 212–229.e12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Martinez-Sanchez, N. et al. Thyroid hormones induce browning of white fat. J. Endocrinol. 232, 351–362 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Seoane-Collazo, P. et al. SF1-specific AMPKalpha1 deletion protects against diet-induced obesity. Diabetes 67, 2213–2226 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Lopez, M. Hypothalamic AMPK and energy balance. Eur. J. Clin. Invest. 48, e12996 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Silva, J. E. & Larsen, P. R. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 305, 712–713 (1983).

    Article  CAS  PubMed  Google Scholar 

  59. Rubio, A., Raasmaja, A., Maia, A. L., Kim, K. R. & Silva, J. E. Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3′,5′-monophosphate generation. Endocrinology 136, 3267–3276 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Weiner, J., Hankir, M., Heiker, J. T., Fenske, W. & Krause, K. Thyroid hormones and browning of adipose tissue. Mol. Cell Endocrinol. 458, 156–159 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Solmonson, A. & Mills, E. M. Uncoupling proteins and the molecular mechanisms of thyroid thermogenesis. Endocrinology 157, 455–462 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lopez, M. & Tena-Sempere, M. Estrogens and the control of energy homeostasis: a brain perspective. Trends Endocrinol. Metab. 26, 411–421 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. de Souza, F. S. et al. The estrogen receptor alpha colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2. Eur. J. Pharmacol. 660, 181–187 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Diano, S., Kalra, S. P., Sakamoto, H. & Horvath, T. L. Leptin receptors in estrogen receptor-containing neurons of the female rat hypothalamus. Brain Res. 812, 256–259 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Hirosawa, M. et al. Ablation of estrogen receptor alpha (ERalpha) prevents upregulation of POMC by leptin and insulin. Biochem. Biophys. Res. Commun. 371, 320–323 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Martinez de Morentin, P. B. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Miao, Y. F. et al. An ERbeta agonist induces browning of subcutaneous abdominal fat pad in obese female mice. Sci. Rep. 6, 38579 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rodriguez-Cuenca, S. et al. Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status. Cell Physiol. Biochem. 20, 877–886 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Palin, S. L. et al. 17Beta-estradiol and anti-estrogen ICI:compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes. Metabolism 52, 383–388 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Pedersen, S. B., Kristensen, K., Hermann, P. A., Katzenellenbogen, J. A. & Richelsen, B. Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J. Clin. Endocrinol. Metab. 89, 1869–1878 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Monjo, M., Rodriguez, A. M., Palou, A. & Roca, P. Direct effects of testosterone, 17 beta-estradiol, and progesterone on adrenergic regulation in cultured brown adipocytes: potential mechanism for gender-dependent thermogenesis. Endocrinology 144, 4923–4930 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Rodriguez, A. M., Monjo, M., Roca, P. & Palou, A. Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. Cell Mol. Life Sci. 59, 1714–1723 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Lapid, K., Lim, A., Clegg, D. J., Zeve, D. & Graff, J. M. Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. Nat. Commun. 5, 5196 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Goke, R., Fehmann, H. C. & Goke, B. Glucagon-like peptide-1(7-36) amide is a new incretin/enterogastrone candidate. Eur. J. Clin. Invest. 21, 135–144 (1991).

    Article  CAS  PubMed  Google Scholar 

  77. Beiroa, D. et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Nogueiras, R. et al. Direct control of peripheral lipid deposition by CNS GLP-1 receptor sigaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. J. Neurosci. 29, 5916–5925 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen, J. et al. GLP-1/GLP-1R signaling in regulation of adipocyte differentiation and lipogenesis. Cell Physiol. Biochem. 42, 1165–1176 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Challa, T. D. et al. Regulation of adipocyte formation by GLP-1/GLP-1R signaling. J. Biol. Chem. 287, 6421–6430 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Krieger, J. P. et al. Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R708–R720 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lopez, M., Tena-Sempere, M. & Dieguez, C. Cross-talk between orexins (hypocretins) and the neuroendocrine axes (hypothalamic-pituitary axes). Front. Neuroendocrinol. 31, 113–127 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Backberg, M., Hervieu, G., Wilson, S. & Meister, B. Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur. J. Neurosci. 15, 315–328 (2002).

    Article  PubMed  Google Scholar 

  84. Berthoud, H. R., Patterson, L. M., Sutton, G. M., Morrison, C. & Zheng, H. Orexin inputs to caudal raphe neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem. Cell Biol. 123, 147–156 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Sellayah, D., Bharaj, P. & Sikder, D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab. 14, 478–490 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Pino, M. F., Divoux, A., Simmonds, A. V., Smith, S. R. & Sparks, L. M. Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue. Int. J. Obes. 41, 1646–1653 (2017).

    Article  CAS  Google Scholar 

  87. Digby, J. E. et al. Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B. J. Endocrinol. 191, 129–136 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McLaughlin, T., Ackerman, S. E., Shen, L. & Engleman, E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J. Clin. Invest. 127, 5–13 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lumeng, C. N., DelProposto, J. B., Westcott, D. J. & Saltiel, A. R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57, 3239–3246 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Stein, M., Keshav, S., Harris, N. & Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Kratz, M. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 20, 614–625 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sartipy, P. & Loskutoff, D. J. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 100, 7265–7270 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sartipy, P. & Loskutoff, D. J. Expression profiling identifies genes that continue to respond to insulin in adipocytes made insulin-resistant by treatment with tumor necrosis factor-alpha. J. Biol. Chem. 278, 52298–52306 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Amano, S. U. et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19, 162–171 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Inouye, K. E. et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56, 2242–2250 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Kirk, E. A., Sagawa, Z. K., McDonald, T. O., O’Brien, K. D. & Heinecke, J. W. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 57, 1254–1261 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Bai, Y. & Sun, Q. Macrophage recruitment in obese adipose tissue. Obes. Rev. 16, 127–136 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Erridge, C. & Samani, N. J. Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler. Thromb. Vasc. Biol. 29, 1944–1949 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Huang, S. et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 53, 2002–2013 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Rogero, M. M. & Calder, P. C. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients 10, E432 (2018).

    Article  PubMed  CAS  Google Scholar 

  109. Saberi, M. et al. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10, 419–429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kosteli, A. et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J. Clin. Invest. 120, 3466–3479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pasarica, M. et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58, 718–725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Morigny, P., Houssier, M., Mouisel, E. & Langin, D. Adipocyte lipolysis and insulin resistance. Biochimie 125, 259–266 (2016).

    Article  CAS  PubMed  Google Scholar 

  113. Sun, K., Tordjman, J., Clement, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fujisaka, S. et al. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia 56, 1403–1412 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, Y. S. et al. Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity. Cell 157, 1339–1352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yin, J. et al. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am. J. Physiol. Endocrinol. Metab. 296, E333–E342 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Engin, A. Adipose tissue hypoxia in obesity and its impact on preadipocytes and macrophages: hypoxia hypothesis. Adv. Exp. Med. Biol. 960, 305–326 (2017).

    Article  CAS  PubMed  Google Scholar 

  118. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  119. Miles, P. D. et al. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 46, 1678–1683 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Tang, X. et al. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc. Natl Acad. Sci. USA 103, 2087–2092 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ruan, H., Hacohen, N., Golub, T. R., Van Parijs, L. & Lodish, H. F. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51, 1319–1336 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F. & Spiegelman, B. M. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J. Biol. Chem. 271, 13018–13022 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Ruan, H. et al. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 51, 3176–3188 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Dahlman, I. et al. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha. Diabetes 55, 1792–1799 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Cawthorn, W. P. & Sethi, J. K. TNF-alpha and adipocyte biology. FEBS Lett. 582, 117–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Fischer, K. et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat. Med. 23, 623–630 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Reitman, M. L. How does fat transition from white to beige? Cell Metab. 26, 14–16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bolus, W. R. et al. Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol. Metab. 8, 86–95 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Molofsky, A. B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hams, E., Locksley, R. M., McKenzie, A. N. & Fallon, P. G. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J. Immunol. 191, 5349–5353 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Nguyen, M. T. et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J. Biol. Chem. 282, 35279–35292 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Lee, B. C. et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 23, 685–698 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105–120 (2018).

    Article  CAS  PubMed  Google Scholar 

  140. Tsiotra, P. C., Pappa, V., Raptis, S. A. & Tsigos, C. Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin’s actions. Metabolism 49, 1537–1541 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Mattioli, B., Straface, E., Quaranta, M. G., Giordani, L. & Viora, M. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J. Immunol. 174, 6820–6828 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Zhao, Y., Sun, R., You, L., Gao, C. & Tian, Z. Expression of leptin receptors and response to leptin stimulation of human natural killer cell lines. Biochem. Biophys. Res. Commun. 300, 247–252 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Caldefie-Chezet, F., Poulin, A., Tridon, A., Sion, B. & Vasson, M. P. Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action? J. Leukoc. Biol. 69, 414–418 (2001).

    CAS  PubMed  Google Scholar 

  144. Kato, H. et al. Leptin has a priming effect on eotaxin-induced human eosinophil chemotaxis. Int. Arch. Allergy Immunol. 155, 335–344 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Suzukawa, M. et al. Leptin enhances survival and induces migration, degranulation, and cytokine synthesis of human basophils. J. Immunol. 186, 5254–5260 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Dib, L. H., Ortega, M. T., Fleming, S. D., Chapes, S. K. & Melgarejo, T. Bone marrow leptin signaling mediates obesity-associated adipose tissue inflammation in male mice. Endocrinology 155, 40–46 (2014).

    Article  PubMed  CAS  Google Scholar 

  147. Gutierrez, D. A. & Hasty, A. H. Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity. J. Endocrinol. 212, 343–351 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Gove, M. E., Sherry, C. L., Pini, M. & Fantuzzi, G. Generation of leptin receptor bone marrow chimeras: recovery from irradiation, immune cellularity, cytokine expression, and metabolic parameters. Obesity 18, 2274–2281 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Acedo, S. C., Gambero, S., Cunha, F. G., Lorand-Metze, I. & Gambero, A. Participation of leptin in the determination of the macrophage phenotype: an additional role in adipocyte and macrophage crosstalk. In Vitro Cell Dev. Biol. Anim. 49, 473–478 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Wong, C. K., Cheung, P. F. & Lam, C. W. Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation. Eur. J. Immunol. 37, 2337–2348 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Santos-Alvarez, J., Goberna, R. & Sanchez-Margalet, V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol. 194, 6–11 (1999).

    Article  CAS  PubMed  Google Scholar 

  152. Yokota, T. et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96, 1723–1732 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Wulster-Radcliffe, M. C., Ajuwon, K. M., Wang, J., Christian, J. A. & Spurlock, M. E. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem. Biophys. Res. Commun. 316, 924–929 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Wolf, A. M., Wolf, D., Rumpold, H., Enrich, B. & Tilg, H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem. Biophys. Res. Commun. 323, 630–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Ohashi, K. et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J. Biol. Chem. 285, 6153–6160 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Hui, X. et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 22, 279–290 (2015).

    Article  CAS  PubMed  Google Scholar 

  157. Berg, A. H., Combs, T. P., Du, X., Brownlee, M. & Scherer, P. E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Tsatsanis, C. et al. Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem. Biophys. Res. Commun. 335, 1254–1263 (2005).

    Article  CAS  PubMed  Google Scholar 

  159. Cheng, X., Folco, E. J., Shimizu, K. & Libby, P. Adiponectin induces pro-inflammatory programs in human macrophages and CD4+ T cells. J. Biol. Chem. 287, 36896–36904 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Folco, E. J., Rocha, V. Z., Lopez-Ilasaca, M. & Libby, P. Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10. J. Biol. Chem. 284, 25569–25575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Park, P. H., McMullen, M. R., Huang, H., Thakur, V. & Nagy, L. E. Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production. J. Biol. Chem. 282, 21695–21703 (2007).

    Article  CAS  PubMed  Google Scholar 

  162. Fruebis, J. et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc. Natl Acad. Sci. USA 98, 2005–2010 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pajvani, U. B. et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: implications for metabolic regulation and bioactivity. J. Biol. Chem. 278, 9073–9085 (2003).

    Article  CAS  PubMed  Google Scholar 

  164. Kang, K. et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485–495 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ouchi, N. et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 329, 454–457 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Han, C. Y. et al. Adipocyte-derived serum amyloid A3 and hyaluronan play a role in monocyte recruitment and adhesion. Diabetes 56, 2260–2273 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Li, P. et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 21, 239–247 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Spite, M. et al. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J. Immunol. 187, 1942–1949 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Cereijo, R. et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 28, 750–763.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Scanzano, A. & Cosentino, M. Adrenergic regulation of innate immunity: a review. Front. Pharmacol. 6, 171 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Grailer, J. J., Haggadone, M. D., Sarma, J. V., Zetoune, F. S. & Ward, P. A. Induction of M2 regulatory macrophages through the beta2-adrenergic receptor with protection during endotoxemia and acute lung injury. J. Innate. Immun. 6, 607–618 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Noh, H. et al. Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications. Kidney Int. 92, 101–113 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Tan, K. S. et al. Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms. Cell Signal. 19, 251–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  174. Grisanti, L. A. et al. beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. Proc. Natl. Acad Sci. USA 113, 15126–15131 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Shen, H. M., Sha, L. X., Kennedy, J. L. & Ou, D. W. Adrenergic receptors regulate macrophage secretion. Int. J. Immunopharmacol. 16, 905–910 (1994).

    Article  CAS  PubMed  Google Scholar 

  176. Piazza, O. et al. Effect of alpha2-adrenergic agonists and antagonists on cytokine release from human lung macrophages cultured in vitro. Transl Med. UniSa. 15, 67–73 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Silvestri, M., Oddera, S., Lantero, S. & Rossi, G. A. β2-agonist-induced inhibition of neutrophil chemotaxis is not associated with modification of LFA-1 and Mac-1 expression or with impairment of polymorphonuclear leukocyte antibacterial activity. Respir. Med. 93, 416–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  178. Butchers, P. R., Vardey, C. J. & Johnson, M. Salmeterol: a potent and long-acting inhibitor of inflammatory mediator release from human lung. Br. J. Pharmacol. 104, 672–676 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Noguchi, T. et al. Effect of beta2-adrenergic agonists on eosinophil adhesion, superoxide anion generation, and degranulation. Allergol. Int. 64, S46–S53 (2015).

    Article  PubMed  Google Scholar 

  180. Moriyama, S. et al. beta2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056–1061 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Takamoto, T. et al. Norepinephrine inhibits human natural killer cell activity in vitro. Int. J. Neurosci. 58, 127–131 (1991).

    Article  CAS  PubMed  Google Scholar 

  182. Wu, H. et al. beta2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats. Sci. Rep. 6, 24548 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Prinz, M. & Priller, J. The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20, 136–144 (2017).

    Article  CAS  PubMed  Google Scholar 

  184. Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Wolf, Y. et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18, 665–674 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Young, P., Arch, J. R. & Ashwell, M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett. 167, 10–14 (1984).

    Article  CAS  PubMed  Google Scholar 

  187. Cousin, B. et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 (1992).

    Article  CAS  PubMed  Google Scholar 

  188. Fukui, Y., Masui, S., Osada, S., Umesono, K. & Motojima, K. A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice. Diabetes 49, 759–767 (2000).

    Article  CAS  PubMed  Google Scholar 

  189. Sanchez-Gurmaches, J., Hung, C. M. & Guertin, D. A. Emerging complexities in adipocyte origins and identity. Trends Cell Biol. 26, 313–326 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Shabalina, I. G. et al. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 5, 1196–1203 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Barquissau, V. et al. White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways. Mol. Metab. 5, 352–365 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Hanssen, M. J. et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65, 1179–1189 (2016).

    Article  CAS  PubMed  Google Scholar 

  194. Cypess, A. M. et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Patsouris, D. et al. Burn induces browning of the subcutaneous white adipose tissue in mice and humans. Cell Rep. 13, 1538–1544 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sidossis, L. S. et al. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab. 22, 219–227 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Hakansson, M. L., Brown, H., Ghilardi, N., Skoda, R. C. & Meister, B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J. Neurosci. 18, 559–572 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Schwartz, M. W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).

    Article  CAS  PubMed  Google Scholar 

  200. Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–532 (1995).

    Article  CAS  PubMed  Google Scholar 

  201. Korner, J., Savontaus, E., Chua, S. C. Jr., Leibel, R. L. & Wardlaw, S. L. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J. Neuroendocrinol. 13, 959–966 (2001).

    Article  CAS  PubMed  Google Scholar 

  202. 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 

  203. van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M. & Spanswick, D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat. Neurosci. 7, 493–494 (2004).

    Article  PubMed  CAS  Google Scholar 

  204. 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 

  205. Lu, D. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371, 799–802 (1994).

    Article  CAS  PubMed  Google Scholar 

  206. 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 

  207. 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 

  208. Seeley, R. J. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997).

    Article  CAS  PubMed  Google Scholar 

  209. Siegel-Axel, D. I. & Haring, H. U. Perivascular adipose tissue: an unique fat compartment relevant for the cardiometabolic syndrome. Rev. Endocr. Metab. Disord. 17, 51–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  210. Henrichot, E. et al. Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler. Thromb. Vasc. Biol. 25, 2594–2599 (2005).

    Article  CAS  PubMed  Google Scholar 

  211. Withers, S. B. et al. Macrophage activation is responsible for loss of anticontractile function in inflamed perivascular fat. Arterioscler. Thromb. Vasc. Biol. 31, 908–913 (2011).

    Article  CAS  PubMed  Google Scholar 

  212. Yamashita, A. et al. Medial and adventitial macrophages are associated with expansive atherosclerotic remodeling in rabbit femoral artery. Histol. Histopathol. 23, 127–136 (2008).

    CAS  PubMed  Google Scholar 

  213. Almabrouk, T. A. M. et al. High fat diet attenuates the anticontractile activity of aortic PVAT via a mechanism involving AMPK and reduced adiponectin secretion. Front. Physiol. 9, 51 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Greenstein, A. S. et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661–1670 (2009).

    Article  CAS  PubMed  Google Scholar 

  215. Chatterjee, T. K. et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ. Res. 104, 541–549 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Candela, J., Wang, R. & White, C. Microvascular endothelial dysfunction in obesity is driven by macrophage-dependent hydrogen sulfide depletion. Arterioscler. Thromb. Vasc. Biol. 37, 889–899 (2017).

    Article  CAS  PubMed  Google Scholar 

  217. Aghamohammadzadeh, R. et al. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J. Am. Coll. Cardiol. 62, 128–135 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Noblet, J. N., Owen, M. K., Goodwill, A. G., Sassoon, D. J. & Tune, J. D. Lean and obese coronary perivascular adipose tissue impairs vasodilation via differential inhibition of vascular smooth muscle K+ channels. Arterioscler. Thromb. Vasc. Biol. 35, 1393–1400 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    Article  CAS  PubMed  Google Scholar 

  220. Madden, K. S. Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. Dev. Comp. Immunol. 66, 92–97 (2017).

    Article  CAS  PubMed  Google Scholar 

  221. Lopez, M., Nogueiras, R., Tena-Sempere, M. & Dieguez, C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat. Rev. Endocrinol. 12, 421–432 (2016).

    Article  CAS  PubMed  Google Scholar 

  222. Contreras, C., Nogueiras, R., Dieguez, C., Rahmouni, K. & Lopez, M. Traveling from the hypothalamus to the adipose tissue: the thermogenic pathway. Redox. Biol. 12, 854–863 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Jiang, Y., Berry, D. C. & Graff, J. M. Distinct cellular and molecular mechanisms for beta3 adrenergic receptor-induced beige adipocyte formation. eLife 6, e30329 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for the article, contributed to discussion of the content, C.M.L. wrote the article and C.M.L. and A.I.D. reviewed and/or edited the article before submission.

Corresponding author

Correspondence to Ana I. Domingos.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Arborizations

Tree-like, branching arrangement of neuronal processes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Larabee, C.M., Neely, O.C. & Domingos, A.I. Obesity: a neuroimmunometabolic perspective. Nat Rev Endocrinol 16, 30–43 (2020). https://doi.org/10.1038/s41574-019-0283-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-019-0283-6

This article is cited by

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