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Abstract

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

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2021-10-06
2024-10-07
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Literature Cited

  1. Ahrén B. 1999. Plasma leptin and insulin in C57BI/6J mice on a high-fat diet: relation to subsequent changes in body weight. Acta Physiol. Scand. 165:2233–40
    [Google Scholar]
  2. Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM et al. 2014. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19:1162–71
    [Google Scholar]
  3. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE et al. 2004. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:6983–91
    [Google Scholar]
  4. Bamshad M, Aoki VT, Adkison MG, Warren WS, Bartness TJ. 1998. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 275:1R291–99
    [Google Scholar]
  5. Bamshad M, Song CK, Bartness TJ. 1999. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 276:6R1569–78
    [Google Scholar]
  6. Baskin DG, Schwartz MW, Seeley RJ, Woods SC, Porte D et al. 1999. Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus. J. Histochem. Cytochem. 47:3353–62
    [Google Scholar]
  7. Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C et al. 2012. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61:92238–47
    [Google Scholar]
  8. Bjørbæk C, El-Haschimi K, Frantz JD, Flier JS. 1999. The role of SOCS-3 in leptin signaling and leptin resistance. J. Biol. Chem. 274:4230059–65
    [Google Scholar]
  9. Blaszkiewicz M, Willows JW, Dubois AL, Waible S, DiBello K et al. 2019. Neuropathy and neural plasticity in the subcutaneous white adipose depot. PLOS ONE 14:9e0221766
    [Google Scholar]
  10. Bogdonoff MD, Weissler AM, Merritt FL. 1960. The effect of autonomic ganglionic blockade upon serum free fatty acid levels in man. J. Clin. Invest. 39:6959–65
    [Google Scholar]
  11. Bolus WR, Kennedy AJ, Hasty AH. 2018a. Obesity-induced reduction of adipose eosinophils is reversed with low-calorie dietary intervention. Physiol. Rep. 6:22e13919
    [Google Scholar]
  12. Bolus WR, Peterson KR, Hubler MJ, Kennedy AJ, Gruen ML, Hasty AH. 2018b. Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments. Mol. Metab. 8:86–95
    [Google Scholar]
  13. Bornstein SR, Abu-Asab M, Glasow A, Päth G, Hauner H et al. 2000. Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes 49:4532–38
    [Google Scholar]
  14. Bowers RR, Festuccia WTL, Song CK, Shi H, Migliorini RH, Bartness TJ. 2004. Sympathetic innervation of white adipose tissue and its regulation of fat cell number. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286:6R1167–75
    [Google Scholar]
  15. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA et al. 2015. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:7542242–46
    [Google Scholar]
  16. Brestoff JR, Wilen CB, Moley JR, Li Y, Zou W et al. 2021. Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab 33:2270–82.e8
    [Google Scholar]
  17. Brito NA, Brito MN, Bartness TJ. 2008. Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294:5R1445–52
    [Google Scholar]
  18. Callaway EM, Luo L. 2015. Monosynaptic circuit tracing with glycoprotein-deleted rabies viruses. J. Neurosci. 35:248979–85
    [Google Scholar]
  19. Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY et al. 2017. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550:7674119–23
    [Google Scholar]
  20. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. 1995. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:5223546–49
    [Google Scholar]
  21. Cao Y, Wang H, Zeng W. 2018. Whole-tissue 3D imaging reveals intra-adipose sympathetic plasticity regulated by NGF-TrkA signal in cold-induced beiging. Protein Cell 9:6527–39
    [Google Scholar]
  22. Ceccarini G, Flavell RR, Butelman ER, Synan M, Willnow TE et al. 2009. PET imaging of leptin biodistribution and metabolism in rodents and primates. Cell Metab 10:2148–59
    [Google Scholar]
  23. Chen K-HE, Lainez NM, Coss D. 2020. Sex differences in macrophage responses to obesity-mediated changes determine migratory and inflammatory traits. J. Immunol. 206:1141–53
    [Google Scholar]
  24. Chi J, Crane A, Wu Z, Cohen P. 2018a. Adipo-clear: a tissue clearing method for three-dimensional imaging of adipose tissue. J. Vis. Exp. 2018.137e58271
    [Google Scholar]
  25. Chi J, Wu Z, Choi CHJ, Nguyen L, Tegegne S et al. 2018b. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab 27:1226–36.e3
    [Google Scholar]
  26. Chmelař J, Chatzigeorgiou A, Chung K-J, Prucnal M, Voehringer D et al. 2016. No role for mast cells in obesity-related metabolic dysregulation. Front. Immunol 7:524
    [Google Scholar]
  27. Chu DT, Minh Nguyet NT, Dinh TC, Thai Lien NV, Nguyen KH et al. 2018. An update on physical health and economic consequences of overweight and obesity. Diabetes Metab. Syndr. Clin. Res. Rev. 12:61095–100
    [Google Scholar]
  28. Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC, Peris E, Cui C et al. 2017. Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep 20:133149–61
    [Google Scholar]
  29. Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP et al. 2014. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156:1–2304–16
    [Google Scholar]
  30. Commins SP, Watson PM, Frampton IC, Gettys TW. 2001. Leptin selectively reduces white adipose tissue in mice via a UCP1-dependent mechanism in brown adipose tissue. Am. J. Physiol. Endocrinol. Metab. 280:2E372–77
    [Google Scholar]
  31. Correll JW. 1963. Adipose tissue: ability to respond to nerve stimulation in vitro. Science 140:3565387–88
    [Google Scholar]
  32. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S et al. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:6836480–84
    [Google Scholar]
  33. Cox N, Crozet L, Holtman IR, Loyher P-L, Lazarov Tet al 2021. Diet-regulated production of PDGFcc by macrophages controls energy storage. Science 373:6550eabe9383
    [Google Scholar]
  34. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL et al. 2005. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:104192–99
    [Google Scholar]
  35. Dib LH, Ortega MT, Fleming SD, Chapes SK, Melgarejo T. 2014. Bone marrow leptin signaling mediates obesity-associated adipose tissue inflammation in male mice. Endocrinology 155:140–46
    [Google Scholar]
  36. Ding X, Luo Y, Zhang X, Zheng H, Yang X et al. 2016. IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity. J. Endocrinol. 231:135–48
    [Google Scholar]
  37. El-Haschimi K, Pierroz DD, Hileman SM, Bjørbæk C, Flier JS. 2000. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin. Invest. 105:121827–32
    [Google Scholar]
  38. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. 2008. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49:91894–903
    [Google Scholar]
  39. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. 2004. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145:52273–82
    [Google Scholar]
  40. Fantuzzi G. 2013. Adiponectin in inflammatory and immune-mediated diseases. Cytokine 64:11–10
    [Google Scholar]
  41. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH et al. 1999. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341:12879–84
    [Google Scholar]
  42. Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ et al. 2017. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat. Med. 23:5623–30
    [Google Scholar]
  43. François M, Torres H, Huesing C, Zhang R, Saurage C et al. 2019. Sympathetic innervation of the interscapular brown adipose tissue in mouse. Ann. N. Y. Acad. Sci. 1454:13–13
    [Google Scholar]
  44. Fredholm B, Rosell S. 1968. Effects of adrenergic blocking agents on lipid mobilization from canine subcutaneous adipose tissue after sympathetic nerve stimulation. J. Pharmacol. Exp. Ther. 159:11–7
    [Google Scholar]
  45. Friedman JM. 2019. Leptin and the endocrine control of energy balance. Nat. Metab. 1:754–64
    [Google Scholar]
  46. Gabay C, Dreyer MG, Pellegrinelli N, Chicheportiche R, Meier CA. 2001. Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. J. Clin. Endocrinol. Metab. 86:2783–91
    [Google Scholar]
  47. Galton DJ, Bray GA. 1967. Studies on lipolysis in human adipose cells. J. Clin. Invest. 46:4621–29
    [Google Scholar]
  48. Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjørbæk C. 2012. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLOS ONE 7:1e30485
    [Google Scholar]
  49. Garretson JT, Szymanski LA, Schwartz GJ, Xue B, Ryu V, Bartness TJ. 2016. Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis. Mol. Metab. 5:8626–34
    [Google Scholar]
  50. Ginhoux F, Guilliams M. 2016. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44:3439–49
    [Google Scholar]
  51. Giordano A, Song CK, Bowers RR, Ehlen JC, Frontini A et al. 2006. White adipose tissue lacks significant vagal innervation and immunohistochemical evidence of parasympathetic innervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291:5R1243–55
    [Google Scholar]
  52. Goodner CJ, Tustison WA, Davidson MB, Chu PC, Conway MJ. 1967. Studies of substrate regulation in fasting. I. Evidence for central regulation of lipolysis by plasma glucose mediated by the sympathetic nervous system. Diabetes 16:8576–89
    [Google Scholar]
  53. Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA. 2014. Induction of M2 regulatory macrophages through the β2-adrenergic receptor with protection during endotoxemia and acute lung injury. J. Innate Immun. 6:5607–18
    [Google Scholar]
  54. Grisanti LA, Traynham CJ, Repas AA, Gao E, Koch WJ, Tilley DG 2016. β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. PNAS 113:5215126–31
    [Google Scholar]
  55. Gutierrez DA, Muralidhar S, Feyerabend TB, Herzig S, Rodewald HR. 2015. Hematopoietic kit deficiency, rather than lack of mast cells, protects mice from obesity and insulin resistance. Cell Metab 21:5678–91
    [Google Scholar]
  56. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT et al. 1995. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:5223543–46
    [Google Scholar]
  57. Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK. 2015. IL-33 reverses an obesity-induced deficit in visceral adipose tissue ST2+ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J. Immunol. 194:104777–83
    [Google Scholar]
  58. Harrison L, Schriever SC, Feuchtinger A, Kyriakou E, Baumann P et al. 2019. Fluorescent blood-brain barrier tracing shows intact leptin transport in obese mice. Int. J. Obes. 43:61305–18
    [Google Scholar]
  59. Hasan A, Al-Ghimlas F, Warsame S, Al-Hubail A, Ahmad R et al. 2014. IL-33 is negatively associated with the BMI and confers a protective lipid/metabolic profile in non-diabetic but not diabetic subjects. BMC Immunol 15:19
    [Google Scholar]
  60. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. 1997. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100:2270–78
    [Google Scholar]
  61. Heng TSP, Painter MW, Elpek K, Lukacs-Kornek V, Mauermann N et al. 2008. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9:1091–94
    [Google Scholar]
  62. Hillmer EJ, Zhang H, Li HS, Watowich SS. 2016. STAT3 signaling in immunity. Cytokine Growth Factor Rev 31:1–15
    [Google Scholar]
  63. Huesing C, Qualls-Creekmore E, Lee N, François M, Torres H et al. 2020. Sympathetic innervation of inguinal white adipose tissue in the mouse. J. Comp. Neurol 529:71465–85
    [Google Scholar]
  64. Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M et al. 2008. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J. Biol. Chem. 283:5135715–23
    [Google Scholar]
  65. Jeninga EH, Gurnell M, Kalkhoven E. 2009. Functional implications of genetic variation in human PPARγ. Trends Endocrinol. Metab. 20:8380–87
    [Google Scholar]
  66. Jiang H, Ding X, Cao Y, Wang H, Zeng W. 2017. Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell Metab 26:4686–92.e3
    [Google Scholar]
  67. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T et al. 2006. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281:3626602–14
    [Google Scholar]
  68. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa KI et al. 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116:61494–505
    [Google Scholar]
  69. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K et al. 2008. Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell Metab 7:6485–95
    [Google Scholar]
  70. Kannan H, Hayashida Y, Yamashita H. 1989. Increase in sympathetic outflow by paraventricular nucleus stimulation in awake rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 256:6R1325–30
    [Google Scholar]
  71. Kershaw EE, Flier JS. 2004. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89:62548–56
    [Google Scholar]
  72. Kim J, Chung K, Choi C, Beloor J, Ullah I et al. 2016. Silencing CCR2 in macrophages alleviates adipose tissue inflammation and the associated metabolic syndrome in dietary obese mice. Mol. Ther. Nucleic Acids 5:e280
    [Google Scholar]
  73. Kim JD, Diano S. 2020. A sympathetic treatment for obesity. Cell Metab 31:61043–45
    [Google Scholar]
  74. Kitamura T, Feng Y, Kitamura YI, Chua SC, Xu AW et al. 2006. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat. Med. 12:5534–40
    [Google Scholar]
  75. Klingenspor M, Meywirth A, Stöhr S, Heldmaier G. 1994. Effect of unilateral surgical denervation of brown adipose tissue on uncoupling protein mRNA level and cytochrom-c-oxidase activity in the Djungarian hamster. J. Comp. Physiol. B 163:8664–70
    [Google Scholar]
  76. Knight ZA, Hannan KS, Greenberg ML, Friedman JM. 2010. Hyperleptinemia is required for the development of leptin resistance. PLOS ONE 5:6e11376
    [Google Scholar]
  77. Knights AJ, Vohralik EJ, Houweling PJ, Stout ES, Norton LJ et al. 2020. Eosinophil function in adipose tissue is regulated by Krüppel-like factor 3 (KLF3). Nat. Commun. 11:2922
    [Google Scholar]
  78. Koch CE, Lowe C, Pretz D, Steger J, Williams LM, Tups A. 2014. High-fat diet induces leptin resistance in leptin-deficient mice. J. Neuroendocrinol. 26:258–67
    [Google Scholar]
  79. Korner J, Chua SC, Williams JA, Leibel RL, Wardlaw SL. 1999. Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology 70:6377–83
    [Google Scholar]
  80. Korner J, Savontaus E, Chua SC, Leibel RL, Wardlaw SL. 2001. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J. Neuroendocrinol. 13:11959–66
    [Google Scholar]
  81. Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V et al. 2014. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20:4614–25
    [Google Scholar]
  82. Larabee CM, Neely OC, Domingos AI. 2020. Obesity: a neuroimmunometabolic perspective. Nat. Rev. Endocrinol. 16:30–43
    [Google Scholar]
  83. Lee BC, Kim MS, Pae M, Yamamoto Y, Eberlé D et al. 2016. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 23:4685–98
    [Google Scholar]
  84. Lee E-H, Itan M, Jang J, Gu H-J, Rozenberg P et al. 2018. Eosinophils support adipocyte maturation and promote glucose tolerance in obesity. Sci. Rep. 8:9894
    [Google Scholar]
  85. Leibowitz SF, Hammer NJ, Chang K 1981. Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat. Physiol. Behav. 27:61031–40
    [Google Scholar]
  86. Levin N, Nelson C, Gurney A, Vandleni R, De Sauvage F 1996. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. PNAS 93:41726–30
    [Google Scholar]
  87. Liu J, Divoux A, Sun J, Zhang J, Clément K et al. 2009. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 15:8940–45
    [Google Scholar]
  88. Liu J, Lee J, Mazitschek R, Correspondence UO, Salazar Hernandez MA, Ozcan U 2015. Treatment of obesity with celastrol. Cell 161:999–1011
    [Google Scholar]
  89. Liu K, Yang L, Wang G, Liu J, Zhao X et al. 2021. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab 33:3666–75.e4
    [Google Scholar]
  90. Liu ZJ, Bian J, Zhao YL, Zhang X, Zou N, Li D. 2011. Lentiviral vector-mediated knockdown of SOCS3 in the hypothalamus protects against the development of diet-induced obesity in rats. Diabetes Obes. Metab. 13:10885–92
    [Google Scholar]
  91. Lumeng CN, Bodzin JL, Saltiel AR. 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117:1175–84
    [Google Scholar]
  92. Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. 2008. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57:123239–46
    [Google Scholar]
  93. Macdougall CE, Wood EG, Loschko J. 2018. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 27:588–601.e4
    [Google Scholar]
  94. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH et al. 1995. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1:111155–61
    [Google Scholar]
  95. Mahlakõiv T, Flamar AL, Johnston LK, Moriyama S, Putzel GG et al. 2019. Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33. Sci. Immunol. 4:35eaax0416
    [Google Scholar]
  96. Mahú I, Barateiro A, Rial-Pensado E, Martinéz-Sánchez N, Vaz SH et al. 2020. Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects. Cell Metab 31:61120–35.e7
    [Google Scholar]
  97. Maness LM, Banks WA, Kastin AJ. 2000. Persistence of blood-to-brain transport of leptin in obese leptin-deficient and leptin receptor-deficient mice. Brain Res 873:1165–67
    [Google Scholar]
  98. Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M. 2005. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J. Immunol. 174:116820–28
    [Google Scholar]
  99. McMinn JE, Liu S-M, Liu H, Dragatsis I, Dietrich P et al. 2005. Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am. J. Physiol. Metab. 289:3E403–11
    [Google Scholar]
  100. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. 1996. 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 387:2–3113–16
    [Google Scholar]
  101. Montecucco F, Bianchi G, Gnerre P, Bertolotto M, Dallegri F, Ottonello L. 2006. Induction of neutrophil chemotaxis by leptin: crucial role for p38 and Src kinases. Ann. N. Y. Acad. Sci. 1069:463–71
    [Google Scholar]
  102. Moraes-Vieira PMM, Larocca RA, Bassi EJ, Peron JPS, Andrade-Oliveira V et al. 2014. Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur. J. Immunol. 44:3794–806
    [Google Scholar]
  103. Morris A. 2020. Unravelling novel weight loss mechanisms. Nat. Rev. Endocrinol. 16:343
    [Google Scholar]
  104. Morrison SF, Ramamurthy S, Young JB. 2000. Reduced rearing temperature augments responses in sympathetic outflow to brown adipose tissue. J. Neurosci. 20:249264–71
    [Google Scholar]
  105. Münzberg H, Flier JS, Bjørbæk C. 2004. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145:114880–89
    [Google Scholar]
  106. Münzberg H, Huo L, Nillni EA, Hollenberg AN, Bjørbæk C. 2003. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic Proopiomelanocortin gene expression by leptin. Endocrinology 144:52121–31
    [Google Scholar]
  107. Murano I, Barbatelli G, Giordano A, Cinti S 2009. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J. Anat. 214:1171–78
    [Google Scholar]
  108. Myers MG Jr., Heymsfield SB, Haft C, Kahn BB et al. 2012. Defining clinical leptin resistance - challenges and opportunities. Cell Metab 15:2150–56
    [Google Scholar]
  109. Myers MG Jr., Olson DP. 2012. Central nervous system control of metabolism. Nature 491:7424357–63
    [Google Scholar]
  110. Nakagomi A, Okada S, Yokoyama M, Yoshida Y, Shimizu I et al. 2015. Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation. NPJ Aging Mech. Dis. 1:15009
    [Google Scholar]
  111. Nguyen KD, Qiu Y, Cui X, Goh YPS, Mwangi J et al. 2011. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480:7375104–8
    [Google Scholar]
  112. Nguyen NLT, Randall J, Banfield BW, Bartness TJ. 2014. Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306:6R375–86
    [Google Scholar]
  113. Niijima A. 1998. Afferent signals from leptin sensors in the white adipose tissue of the epididymis, and their reflex effect in the rat. J. Auton. Nerv. Syst. 73:119–25
    [Google Scholar]
  114. Noh H, Yu MR, Kim HJ, Lee JH, Park BW et al. 2017. Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications. Kidney Int 92:1101–13
    [Google Scholar]
  115. Obstfeld AE, Sugaru E, Thearle M, Francisco AM, Gayet C et al. 2010. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59:4916–25
    [Google Scholar]
  116. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V et al. 2007. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447:71481116–20
    [Google Scholar]
  117. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR et al. 2008. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab 7:6496–507
    [Google Scholar]
  118. Oh-I S, Shimizu H, Sato T, Uehara Y, Okada S, Mori M 2005. Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain. Cell Metab 1:5331–41
    [Google Scholar]
  119. Olofsson LE, Unger EK, Cheung CC, Xu AW 2013. Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance. PNAS 110:8E697–706
    [Google Scholar]
  120. Ozata M, Ozdemir IC, Licinio J. 1999. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 84:103686–95
    [Google Scholar]
  121. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S et al. 2009. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:135–51
    [Google Scholar]
  122. Patterson MA, Szatmari EM, Yasuda R 2010. AMPA receptors are exocytosed in stimulated spines and adjacent dendrites in a Ras-ERK-dependent manner during long-term potentiation. PNAS 107:3615951–56
    [Google Scholar]
  123. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D et al. 1995. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:5223540–43
    [Google Scholar]
  124. Pereira MMA, Mahú I, Seixas E, Martinéz-Sánchez N, Kubasova N et al. 2017. A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nat. Commun. 8:14967
    [Google Scholar]
  125. Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sánchez NM et al. 2017. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23:111309–18
    [Google Scholar]
  126. Prieur X, Tung YCL, Griffin JL, Farooqi IS, O'Rahilly S, Coll AP. 2008. Leptin regulates peripheral lipid metabolism primarily through central effects on food intake. Endocrinology 149:115432–39
    [Google Scholar]
  127. Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X et al. 2014. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157:61292–308
    [Google Scholar]
  128. Rached MT, Millership SJ, Pedroni SMA, Choudhury AI, Costa ASH et al. 2019. Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Mol. Metab. 20:38–50
    [Google Scholar]
  129. Rafael J, Herling AW. 2000. Leptin effect in ob/ob mice under thermoneutral conditions depends not necessarily on central satiation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278:3R790–95
    [Google Scholar]
  130. Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M et al. 2015. Leptin receptor signaling in T cells is required for Th17 differentiation. J. Immunol. 194:115253–60
    [Google Scholar]
  131. Rezai-Zadeh K, Yu S, Jiang Y, Laque A, Schwartzenburg C et al. 2014. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol. Metab. 3:7681–93
    [Google Scholar]
  132. Santos-Alvarez J, Goberna R, Sánchez-Margalet V. 1999. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell. Immunol. 194:16–11
    [Google Scholar]
  133. Sartipy P, Loskutoff DJ 2003. Monocyte chemoattractant protein 1 in obesity and insulin resistance. PNAS 100:127265–70
    [Google Scholar]
  134. Sasaki T, Moro K, Kubota T, Kubota N, Kato T et al. 2019. Innate lymphoid cells in the induction of obesity. Cell Rep 28:1202–17.e7
    [Google Scholar]
  135. Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N et al. 2013. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 495:7442524–28
    [Google Scholar]
  136. Scanzano A, Cosentino M. 2015. Adrenergic regulation of innate immunity: a review. Front. Pharmacol. 6:171
    [Google Scholar]
  137. Scarpace PJ, Matheny M. 1998. Leptin induction of UCP1 gene expression is dependent on sympathetic innervation. Am. J. Physiol. Metab. 275:2E259–64
    [Google Scholar]
  138. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D. 1996a. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2:5589–93
    [Google Scholar]
  139. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. 1996b. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98:51101–6
    [Google Scholar]
  140. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA et al. 1997. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46:122119–23
    [Google Scholar]
  141. Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF et al. 2009. Leptin targets in the mouse brain. J. Comp. Neurol. 514:5518–32
    [Google Scholar]
  142. Seale P, Kajimura S, Yang W, Chin S, Rohas LM et al. 2007. Transcriptional control of brown fat determination by PRDM16. Cell Metab 6:138–54
    [Google Scholar]
  143. Shi H, Bartness TJ. 2005. White adipose tissue sensory nerve denervation mimics lipectomy-induced compensatory increases in adiposity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289:2R514–20
    [Google Scholar]
  144. Song CK, Schwartz GJ, Bartness TJ. 2009. Anterograde transneuronal viral tract tracing reveals central sensory circuits from white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296:3R501–11
    [Google Scholar]
  145. Spallanzani RG, Zemmour D, Xiao T, Jayewickreme T, Li C et al. 2019. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Sci. Immunol. 4:35eaaw3658
    [Google Scholar]
  146. Stefanovic-Racic M, Yang X, Turner MS, Mantell BS, Stolz DB et al. 2012. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61:92330–39
    [Google Scholar]
  147. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG et al. 1995. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377:530–32
    [Google Scholar]
  148. Suzukawa M, Nagase H, Ogahara I, Han K, Tashimo H et al. 2011. Leptin enhances survival and induces migration, degranulation, and cytokine synthesis of human basophils. J. Immunol. 186:95254–60
    [Google Scholar]
  149. Svoboda K. 2019. Occasional commentary on the science of neural circuits: using rabies virus for tracing neural connections: caveats and limitations exposed by studies of barrel cortex circuits. Karel Svoboda https://spikesphotons.blog/2019/05/13/using-rabies-virus-for-tracing-neural-connections-caveats-and-limitations-exposed-by-studies-of-barrel-cortex-circuits/
    [Google Scholar]
  150. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J et al. 2012. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18:91407–12
    [Google Scholar]
  151. Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM. 2007. β2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-κB-independent mechanisms. Cell. Signal. 19:2251–60
    [Google Scholar]
  152. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J et al. 1995. Identification and expression cloning of a leptin receptor, OB-R. Cell 83:71263–71
    [Google Scholar]
  153. Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW. 2013. Hypothalamic inflammation: marker or mechanism of obesity pathogenesis?. Diabetes 62:82629–34
    [Google Scholar]
  154. Tsiotra PC, Pappa V, Raptis SA, Tsigos C. 2000. Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin's actions. Metabolism 49:121537–41
    [Google Scholar]
  155. van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R et al. 2008. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149:41773–85
    [Google Scholar]
  156. Versini M, Jeandel P-Y, Rosenthal E, Shoenfeld Y. 2014. Obesity in autoimmune diseases: not a passive bystander. Autoimmun. Rev. 13:9981–1000
    [Google Scholar]
  157. Wang P, Loh KH, Wu M, Morgan DA, Schneeberger M et al. 2020. A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583:7818839–44
    [Google Scholar]
  158. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S et al. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116:1115–24
    [Google Scholar]
  159. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. 2003. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112:121796–808
    [Google Scholar]
  160. Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT et al. 2015. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16:4376–85
    [Google Scholar]
  161. White GE, Cotterill A, Addley MR, Soilleux EJ, Greaves DR. 2011. Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation. J. Mol. Histol. 42:2137–51
    [Google Scholar]
  162. WHO (World Health Organ.) 2020. Obesity and overweight. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
    [Google Scholar]
  163. Wickersham IR, Lyon DC, Barnard RJO, Mori T, Finke S et al. 2007. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53:5639–47
    [Google Scholar]
  164. Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Shalom HS et al. 2017. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18:6665–74
    [Google Scholar]
  165. Wong CK, Cheung PF-Y, Lam CWK. 2007. Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation. Eur. J. Immunol. 37:82337–48
    [Google Scholar]
  166. Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA et al. 2011. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:6026243–47
    [Google Scholar]
  167. Xu H, Barnes GT, Yang Q, Tan G, Yang D et al. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112:121821–30
    [Google Scholar]
  168. Yaron A, Huang PH, Cheng HJ, Tessier-Lavigne M. 2005. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 45:4513–23
    [Google Scholar]
  169. Youngstrom TG, Bartness TJ. 1995. Catecholaminergic innervation of white adipose tissue in Siberian hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 268:3R744–51
    [Google Scholar]
  170. Yu S, Cheng H, François M, Qualls-Creekmore E, Huesing C et al. 2018. Preoptic leptin signaling modulates energy balance independent of body temperature regulation. eLife 7:e33505
    [Google Scholar]
  171. Zarkesh-Esfahani H, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z et al. 2001. High-dose leptin activates human leukocytes via receptor expression on monocytes. J. Immunol. 167:84593–99
    [Google Scholar]
  172. Zeng W, Pirzgalska RM, Pereira MMA, Kubasova N, Barateiro A et al. 2015. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163:184–94
    [Google Scholar]
  173. Zhang K, Kaufman RJ. 2008. From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–62
    [Google Scholar]
  174. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372:6505425–32
    [Google Scholar]
  175. Zhao S, Zhu Y, Schultz RD, Li N, He Z et al. 2019. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab 30:4706–19.e6
    [Google Scholar]
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