Hypothalamic innate immune reaction in obesity

Journal name:
Nature Reviews Endocrinology
Year published:
Published online


Findings from rodent and human studies show that the presence of inflammatory factors is positively correlated with obesity and the metabolic syndrome. Obesity-associated inflammatory responses take place not only in the periphery but also in the brain. The hypothalamus contains a range of resident glial cells including microglia, macrophages and astrocytes, which are embedded in highly heterogenic groups of neurons that control metabolic homeostasis. This complex neural–glia network can receive information directly from blood-borne factors, positioning it as a metabolic sensor. Following hypercaloric challenge, mediobasal hypothalamic microglia and astrocytes enter a reactive state, which persists during diet-induced obesity. In established mouse models of diet-induced obesity, the hypothalamic vasculature displays angiogenic alterations. Moreover, proopiomelanocortin neurons, which regulate food intake and energy expenditure, are impaired in the arcuate nucleus, where there is an increase in local inflammatory signals. The sum total of these events is a hypothalamic innate immune reactivity, which includes temporal and spatial changes to each cell population. Although the exact role of each participant of the neural–glial–vascular network is still under exploration, therapeutic targets for treating obesity should probably be linked to individual cell types and their specific signalling pathways to address each dysfunction with cell-selective compounds.

At a glance


  1. The cytoarchitecture of hypothalamic NPY and POMC neurons, microglia, astrocytes and vasculature.
    Figure 1: The cytoarchitecture of hypothalamic NPY and POMC neurons, microglia, astrocytes and vasculature.

    a | A 3D reconstruction of NPY neurons (green), AIF-1-ir microglia (pink) and GFAP-ir astrocytes (white) in the arcuate nucleus. b | A 3D reconstruction of POMC neuron (green) and microglia (AIF-1-ir, in red) in the arcuate nucleus. c | Blood vessel (red) with microglia/perivascular macrophages (from CX3Cr1-GFP, green) and GFAP-ir astrocytes (blue) in the mediobasal hypothalamus. Asterisks denote location of the third ventricle. Scale bar: 35 µm in a, 50 µm in b and 70 µm in c. Abbreviations: AIF-1, allograft inflammatory factor 1; GFP, green fluorescent protein; GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; NPY, neuropeptide Y; POMC, proopiomelanocortin.

  2. The diversity of hypothalamic microglia and macrophages visualized in CX3Cr1-GFP mice.
    Figure 2: The diversity of hypothalamic microglia and macrophages visualized in CX3Cr1-GFP mice.

    a | Microglia and macrophages in different locations of the mediobasal hypothalamus. b | NPY neurons (from NPY-GFP mice, in green) extend into the internal zone of the ME, while microglia (by AIF-1-ir in red) are densely distributed throughout the entire ME. c | The cytoarchitecture of microglia and macrophages (in green), astrocytes and tanycytes (GFAP-ir, in red) in the IZ and EZ of the ME (indicated by DAPI in blue). The white arrows point to macrophage-like cells in the EZ of the ME. d | GFP+ (green) or AIF-1-ir+ (red) microglia and macrophages in the ME, white arrow points to a CX3CR1+ cell without AIF-1-ir in the EZ of the ME. e | Two perivascular GFP+CX3CR1+ cells (indicated by white arrows) tightly apposed to blood vessels (in blue) in the mediobasal hypothalamus. 'Merge', shown in yellow, indicates microglia and macrophages that are positive for GFP and AIF-ir. Asterisks denote location of the third ventricle. Scale bar: 70 µm in b, 50 µm in c and d and 20 µm in e. Abbreviations: AIF-1, allograft inflammatory factor 1; EZ, external zone; GFP, green fluorescent protein; GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; IZ, internal zone; ME, median eminence; NPY, neuropeptide Y.

  3. Morphological comparison of microglial reactivity in diet-induced obesity as visualized by AIF-1-ir.
    Figure 3: Morphological comparison of microglial reactivity in diet-induced obesity as visualized by AIF-1-ir.

    a | Reactivity in chow-fed mice. b | Reactivity in 8-month old mice fed a high-fat diet. Peripheral nerve injury in c | control mice and d | injured mice. e | Mediobasal hypothalamus injected with lentivirus carrying an empty vector at a concentration of 108/ml, and 1 µl was injected in the mediobasal hypothalamus of wild-type C57BL/6 mice. f | Mediobasal hypothalamus mechanically injured with a 32 gauge needle used for virus injection. The high-fat diet induced microglial reactivity, visualized by ramification and soma size, is comparable to those by peripheral nerve injury or mechanical injury, but much less than those activated by infectious lentivirus. Scale bar: 20 µm. Abbreviation: AIF-1, allograft inflammatory factor 1.

  4. The distribution pattern of the GFP+ astrocytes (green) and GFAP-ir astrocytes (red) in hGFAP-GFP transgenic mouse hypothalamus.
    Figure 4: The distribution pattern of the GFP+ astrocytes (green) and GFAP-ir astrocytes (red) in hGFAP-GFP transgenic mouse hypothalamus.

    Abbreviations: GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; GFP, green fluorescent protein.

  5. The diverse cell populations in the local microenvironment of the mediobasal hypothalamus and their respective transitions from basal conditions to reactive stages in the metabolic syndrome.
    Figure 5: The diverse cell populations in the local microenvironment of the mediobasal hypothalamus and their respective transitions from basal conditions to reactive stages in the metabolic syndrome.

    With exposure to a hypercaloric environment, microglia and astrocytes rapidly enter reactive states. Peripheral monocytes might also infiltrate this area as part of the local microenvironment immune response. In the long term, the communication between neurons and the general circulation is hampered by astrocytosis and angiogenic factors derived from the local microenvironment, which drive angiogenesis. The cell-specific antiobesity therapeutic strategy of targeting cells expressing the glucagon-like peptide 1 receptor with metabolically beneficial estradiol is effective, depending on the specific intercellular and intracellular mechanisms. This strategy confers the benefits of estrogen without the unwanted adverse effects. To specifically target reactive microglia, a conjugate in which fractalkine can carry anti-inflammatory steroids (such as dexamethasone) into the microglia is proposed.


  1. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425432 (1994).
  2. Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 13501355 (2012).
  3. Begg, D. P. & Woods, S. C. The endocrinology of food intake. Nat. Rev. Endocrinol. 9, 584597 (2013).
  4. Furuhashi, M. et al. Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J. Clin. Invest. 118, 26402650 (2008).
  5. Mathis, D. Immunological goings-on in visceral adipose tissue. Cell Metab. 17, 851859 (2013).
  6. Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 6173 (2008).
  7. De Souza, C. T. et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146, 41924199 (2005).
  8. Yi, C. X., Zeltser, L. & Tschöp, M. H. Metabolic Syndrome ePoster—Brain & Neuron. Nat. Med. [online], (2011).
  9. Yi, C. X. & Tschöp, M. H. Brain-gut-adipose-tissue communication pathways at a glance. Dis. Model. Mech. 5, 583587 (2012).
  10. Yi, C. X., Scherer, T. & Tschöp, M. H. Cajal revisited: does the VMH make us fat? Nat. Neurosci. 14, 806808 (2011).
  11. Kim, K. W. et al. CNS-specific ablation of steroidogenic factor 1 results in impaired female reproductive function. Mol. Endocrinol. 24, 12401250 (2010).
  12. Xu, B. et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6, 736742 (2003).
  13. Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 13761382 (2002).
  14. Bruinstroop, E. et al. The autonomic nervous system regulates postprandial hepatic lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 304, E1089E1096 (2013).
  15. Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320327 (2005).
  16. Cottrell, G. T. & Ferguson, A. V. Sensory circumventricular organs: central roles in integrated autonomic regulation. Regul. Pept. 117, 1123 (2004).
  17. Milanski, M. et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359370 (2009).
  18. Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153162 (2012).
  19. Yi, C. X. et al. High calorie diet triggers hypothalamic angiopathy. Mol. Metab. 1, 95100 (2012).
  20. Moraes, J. C. et al. High-fat diet induces apoptosis of hypothalamic neurons. PLoS ONE 4, e5045 (2009).
  21. Li, J., Tang, Y. & Cai, D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat. Cell Biol. 14, 9991012 (2012).
  22. Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463477 (2014).
  23. Heppner, F., Ransohoff, R. & Becher, B. Immune attack! The role of inflammation in Alzheimer's disease. Nat. Rev. Neurosci. (in press).
  24. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841845 (2010).
  25. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273280 (2013).
  26. Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145152 (1999).
  27. Perry, V. H., Hume, D. A. & Gordon, S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313326 (1985).
  28. Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 9941008 (2007).
  29. Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 15441553 (2007).
  30. Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl Acad. Sci. USA 109, 1815018155 (2012).
  31. Li, Y., Du, X. F., Liu, C. S., Wen, Z. L. & Du, J. L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 11891202 (2012).
  32. Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300312 (2014).
  33. Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461553 (2011).
  34. Daikoku, S., Kotsu, T. & Hashimoto, M. Electron microscopic observations on the development of the median eminence in perinatal rats. Z. Anat. Entwicklungsgesch. 134, 311327 (1971).
  35. Bitsch, P. & Schiebler, T. H. Postnatal development of the median eminence in the rat [German]. Z. Mikrosk. Anat. Forsch. 93, 120 (1979).
  36. Pow, D. V., Perry, V. H., Morris, J. F. & Gordon, S. Microglia in the neurohypophysis associate with and endocytose terminal portions of neurosecretory neurons. Neuroscience 33, 567578 (1989).
  37. Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 41064114 (2000).
  38. Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 12611266 (2009).
  39. Grossmann, R. et al. Juxtavascular microglia migrate along brain microvessels following activation during early postnatal development. Glia 37, 229240 (2002).
  40. Davalos, D. et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat. Commun. 3, 1227 (2012).
  41. Neumann, H., Kotter, M. R. & Franklin, R. J. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288295 (2009).
  42. Douglas, S. D. & Musson, R. A. Phagocytic defects--monocytes/macrophages. Clin. Immunol. Immunopathol. 40, 6268 (1986).
  43. Vedeler, C. et al. Fc receptor for IgG (FcR) on rat microglia. J. Neuroimmunol. 49, 1924 (1994).
  44. Quan, Y., Moller, T. & Weinstein, J. R. Regulation of Fcγ receptors and immunoglobulin G-mediated phagocytosis in mouse microglia. Neurosci. Lett. 464, 2933 (2009).
  45. Webster, S. D., Park, M., Fonseca, M. I. & Tenner, A. J. Structural and functional evidence for microglial expression of C1qRP, the C1q receptor that enhances phagocytosis. J. Leukoc. Biol. 67, 109116 (2000).
  46. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916919 (2000).
  47. Citron, M. Alzheimer's disease: strategies for disease modification. Nat. Rev. Drug Discov. 9, 387398 (2010).
  48. Fishman, P. S. & Savitt, J. M. Selective localization by neuroglia of immunoglobulin G in normal mice. J. Neuropathol. Exp. Neurol. 48, 212220 (1989).
  49. Yi, C. X., Tschöp, M. H., Woods, S. C. & Hofmann, S. M. High-fat-diet exposure induces IgG accumulation in hypothalamic microglia. Dis. Model. Mech. 5, 686690 (2012).
  50. Ferreira, R. et al. Neuropeptide Y inhibits interleukin-1β-induced phagocytosis by microglial cells. J. Neuroinflammation 8, 169 (2011).
  51. Krabbe, G. et al. Functional impairment of microglia coincides with β-amyloid deposition in mice with Alzheimer-like pathology. PLoS ONE 8, e60921 (2013).
  52. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 39743980 (2009).
  53. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 14561458 (2011).
  54. Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400406 (2014).
  55. Bouret, S. G., Draper, S. J. & Simerly, R. B. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J. Neurosci. 24, 27972805 (2004).
  56. Loffreda, S. et al. Leptin regulates proinflammatory immune responses. FASEB J. 12, 5765 (1998).
  57. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691705 (2012).
  58. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 13141318 (2005).
  59. Schaeffer, M. et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc. Natl Acad. Sci. USA 110, 15121517 (2013).
  60. Gao, Y. et al. Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62, 1725 (2014).
  61. Lafrance, V., Inoue, W., Kan, B. & Luheshi, G. N. Leptin modulates cell morphology and cytokine release in microglia. Brain Behav. Immun. 24, 358365 (2010).
  62. Kleinridders, A. et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249259 (2009).
  63. Choi, S. J., Kim, F., Schwartz, M. W. & Wisse, B. E. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am. J. Physiol. Endocrinol. Metab. 298, E1122E1130 (2010).
  64. Douard, V. & Ferraris, R. P. Regulation of the fructose transporter GLUT5 in health and disease. Am. J. Physiol. Endocrinol. Metab. 295, E227E237 (2008).
  65. Maher, F., Vannucci, S. J. & Simpson, I. A. Glucose transporter proteins in brain. FASEB J. 8, 10031011 (1994).
  66. Vannucci, S. J., Maher, F. & Simpson, I. A. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21, 221 (1997).
  67. Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat. Med. 18, 18121819 (2012).
  68. Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707720 (2013).
  69. Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 118, 475485 (2009).
  70. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 15961609 (2013).
  71. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 1469114696 (2010).
  72. Zhao, L. The gut microbiota and obesity: from correlation to causality. Nat. Rev. Microbiol. 11, 639647 (2013).
  73. Inoue, K. Microglial activation by purines and pyrimidines. Glia 40, 156163 (2002).
  74. James, G. & Butt, A. M. P2Y and P2X purinoceptor mediated Ca2+ signalling in glial cell pathology in the central nervous system. Eur. J. Pharmacol. 447, 247260 (2002).
  75. Samuels, S. E., Lipitz, J. B., Wang, J., Dahl, G. & Muller, K. J. Arachidonic acid closes innexin/pannexin channels and thereby inhibits microglia cell movement to a nerve injury. Dev. Neurobiol. 73, 621631 (2013).
  76. Bermudez-Silva, F. J., Cardinal, P. & Cota, D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J. Psychopharmacol. 26, 114124 (2012).
  77. Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917924 (2006).
  78. Morari, J. et al. Fractalkine (CX3CL1) is involved in the early activation of hypothalamic inflammation in experimental obesity. Diabetes 63, 37703784 (2014).
  79. Ruchaya, P. J., Antunes, V. R., Paton, J. F., Murphy, D. & Yao, S. T. The cardiovascular actions of fractalkine/CX3CL1 in the hypothalamic paraventricular nucleus are attenuated in rats with heart failure. Exp. Physiol. 99, 111122 (2014).
  80. Buckman, L. B. et al. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav. Immun. 35, 3342 (2014).
  81. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 1115911171 (2011).
  82. Kierdorf, K., Katzmarski, N., Haas, C. A. & Prinz, M. Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS ONE 8, e58544 (2013).
  83. Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 2335 (2003).
  84. Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723737 (2011).
  85. Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E. & Heuschling, P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-β. J. Neuroimmunol. 210, 312 (2009).
  86. Ponomarev, E. D., Maresz, K., Tan, Y. & Dittel, B. N. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J. Neurosci. 27, 1071410721 (2007).
  87. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 12271235 (2011).
  88. Town, T., Nikolic, V. & Tan, J. The microglial “activation” continuum: from innate to adaptive responses. J. Neuroinflammation 2, 24 (2005).
  89. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 1420 (2014).
  90. Wieghofer, P., Knobeloch, K. P. & Prinz, M. Genetic targeting of microglia. Glia 63, 122 (2014).
  91. Goldmann, T. et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 16181626 (2013).
  92. Heppner, F. L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146152 (2005).
  93. Grathwohl, S. A. et al. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 13611363 (2009).
  94. Yi, C. X., Habegger, K. M., Chowen, J. A., Stern, J. & Tschöp, M. H. A role for astrocytes in the central control of metabolism. Neuroendocrinology 93, 143149 (2011).
  95. Broer, S. et al. Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J. Biol. Chem. 272, 3009630102 (1997).
  96. Le Foll, C., Dunn-Meynell, A. A., Miziorko, H. M. & Levin, B. E. Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63, 12591269 (2014).
  97. Dixit, V. D. et al. Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J. Biol. Chem. 281, 1668116690 (2006).
  98. Hsuchou, H. et al. Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain 132, 889902 (2009).
  99. Heni, M. et al. Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 6, e21594 (2011).
  100. Kim, J. G. et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908910 (2014).
  101. Diano, S., Leonard, J. L., Meli, R., Esposito, E. & Schiavo, L. Hypothalamic type II iodothyronine deiodinase: a light and electron microscopic study. Brain Res. 976, 130134 (2003).
  102. Herwig, A., Ross, A. W., Nilaweera, K. N., Morgan, P. J. & Barrett, P. Hypothalamic thyroid hormone in energy balance regulation. Obes. Facts 1, 7179 (2008).
  103. Courtin, F. et al. Thyroid hormone deiodinases in the central and peripheral nervous system. Thyroid 15, 931942 (2005).
  104. Kamphuis, W. et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS ONE 7, e42823 (2012).
  105. Horvath, T. L. et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc. Natl Acad. Sci. USA 107, 1487514880 (2010).
  106. Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 13111314 (1995).
  107. Campbell, I. L. et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl Acad. Sci. USA 90, 1006110065 (1993).
  108. Haugh, R. M. & Markesbery, W. R. Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function. Arch. Neurol. 40, 560563 (1983).
  109. Emsley, J. G. & Macklis, J. D. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol. 2, 175186 (2006).
  110. Langlet, F. et al. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab. 17, 607617 (2013).
  111. Milanski, M. et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61, 14551462 (2012).
  112. 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, 8791 (1993).
  113. Ventre, J. et al. Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 15261531 (1997).
  114. Pamir, N., McMillen, T. S., Kaiyala, K. J., Schwartz, M. W. & LeBoeuf, R. C. Receptors for tumor necrosis factor-α play a protective role against obesity and alter adipose tissue macrophage status. Endocrinology 150, 41244134 (2009).
  115. Aggarwal, B. B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745756 (2003).
  116. Baker, R. G., Hayden, M. S. & Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab. 13, 1122 (2011).
  117. Perkins, N. D. Integrating cell-signalling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell Biol. 8, 4962 (2007).
  118. Meng, Q. & Cai, D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase β (IKKβ)/NF-κB pathway. J. Biol. Chem. 286, 3232432332 (2011).
  119. Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17, 883887 (2011).
  120. Koulich, E., Nguyen, T., Johnson, K., Giardina, C. & D'Mello, S. NF-κB is involved in the survival of cerebellar granule neurons: association of Iκβ phosphorylation with cell survival. J. Neurochem. 76, 11881198 (2001).
  121. Culmsee, C. et al. Reciprocal inhibition of p53 and nuclear factor-κB transcriptional activities determines cell survival or death in neurons. J. Neurosci. 23, 85868595 (2003).
  122. Kuno, R. et al. Autocrine activation of microglia by tumor necrosis factor-α. J. Neuroimmunol. 162, 8996 (2005).
  123. Listwak, S. J., Rathore, P. & Herkenham, M. Minimal NF-κB activity in neurons. Neuroscience 250, 282299 (2013).
  124. Tantiwong, P. et al. NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions. Am. J. Physiol. Endocrinol. Metab. 299, E794E801 (2010).
  125. Dietrich, M. O. & Horvath, T. L. Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci. 36, 6573 (2013).
  126. Zeltser, L. M., Seeley, R. J. & Tschöp, M. H. Synaptic plasticity in neuronal circuits regulating energy balance. Nat. Neurosci. 15, 13361342 (2012).
  127. Mattson, M. P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748766 (2008).
  128. Chang, D. T., Honick, A. S. & Reynolds, I. J. Mitochondrial trafficking to synapses in cultured primary cortical neurons. J. Neurosci. 26, 70357045 (2006).
  129. Sheng, Z. H. & Cai, Q. Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat. Rev. Neurosci. 13, 7793 (2012).
  130. de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605610 (2008).
  131. Vannuvel, K., Renard, P., Raes, M. & Arnould, T. Functional and morphological impact of ER stress on mitochondria. J. Cell. Physiol. 228, 18021818 (2013).
  132. Schneeberger, M. et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172187 (2013).
  133. Diano, S. et al. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat. Med. 17, 11211127 (2011).
  134. Dietrich, M. O., Liu, Z. W. & Horvath, T. L. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155, 188199 (2013).
  135. Cnop, M. et al. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54 (Suppl.2), S97S107 (2005).
  136. Schapira, A. H., Olanow, C. W., Greenamyre, J. T. & Bezard, E. Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. Lancet 384, 545555 (2014).
  137. Alkemade, A. et al. AgRP and NPY expression in the human hypothalamic infundibular nucleus correlate with body mass index, whereas changes in αMSH are related to type 2 diabetes. J. Clin. Endocrinol. Metab. 97, E925E933 (2012).
  138. Watkins, L. R. & Hutchinson, M. R. A concern on comparing 'apples' and 'oranges' when differences between microglia used in human and rodent studies go far, far beyond simply species: comment on Smith and Dragunow. Trends Neurosci. 37, 189190 (2014).
  139. Smith, A. M. & Dragunow, M. The human side of microglia. Trends Neurosci. 37, 125135 (2014).
  140. Finan, B. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 18471856 (2012).
  141. Komm, B. S. & Mirkin, S. An overview of current and emerging SERMs. J. Steroid Biochem. Mol. Biol. 143, 207222 (2014).
  142. van der Goes, A., Hoekstra, K., van den Berg, T. K. & Dijkstra, C. D. Dexamethasone promotes phagocytosis and bacterial killing by human monocytes/macrophages in vitro. J. Leukoc. Biol. 67, 801807 (2000).
  143. Caro, J. F. & Amatruda, J. M. Glucocorticoid-induced insulin resistance: the importance of postbinding events in the regulation of insulin binding, action, and degradation in freshly isolated and primary cultures of rat hepatocytes. J. Clin. Invest. 69, 866875 (1982).
  144. Kennedy, B., Elayan, H. & Ziegler, M. G. Glucocorticoid induction of epinephrine synthesizing enzyme in rat skeletal muscle and insulin resistance. J. Clin. Invest. 92, 303307 (1993).
  145. Yi, C. X. et al. Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. Diabetes 61, 339345 (2012).

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Author information


  1. Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, 85748, Munich, Germany.

    • Stefanie Kälin &
    • Matthias H. Tschöp
  2. Department of Neuropathology, Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany.

    • Frank L. Heppner
  3. Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany.

    • Ingo Bechmann
  4. Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany.

    • Marco Prinz
  5. Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands.

    • Chun-Xia Yi


M.H.T. and C.-X.Y. provided substantial contribution to discussion of the content. S.K. and C.-X.Y. wrote the article. F.L.H., I.B., M.P., M.H.T. and C.-X.Y. reviewed and edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

Corresponding author

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Author details

  • Stefanie Kälin

    Dr Stefanie Kälin is a Postdoc in the neuroendocrinology group at the Institute for Diabetes and Obesity, affiliated to the Helmholtz Diabetes Center Munich, Germany. She received her PhD from the Humboldt University Berlin (2010–2014) working at the Charité Hospital as a member of the international Max Planck Research School. Her principal research interest is the pathophysiology of the metabolic syndrome in rodent models, with particular reference to immune regulatory circuits in the central nervous system.

  • Frank L. Heppner

    Frank L. Heppner, MD, is Professor of Neuropathology and Director of the Department of Neuropathology at the Charité–Universitätsmedizin Berlin, Germany. His research group aims to understand microglia biology in health and disease and studies the impact of the immune system on the pathogenesis of neurological disorders such as neurodegenerative diseases, ultimately aimed at recognizing novel therapeutic strategies and targets to treat these central nervous system diseases.

  • Ingo Bechmann

    Dr Ingo Bechmann is the Director of the Institute of Anatomy, Universität Leipzig, Germany. His group has been working in the field of neuroimmunology with a particular focus on immune tolerance in the brain ('immune privilege'), microglial and the blood–brain barrier.

  • Marco Prinz

    Marco Prinz is Professor of Neuropathology and Director of the Institute of Neuropathology at the University of Freiburg, Germany. His laboratory focuses on the development and molecular pathogenesis of disease. He co-chairs the Research Unit 1336 'From monocytes to brain macrophages: conditions influencing the fate of myeloid cells in the brain', which is funded by the German Research Foundation.

  • Matthias H. Tschöp

    Dr Matthias H. Tschöp is the Director of the Institute for Diabetes and Obesity at Helmholtz Center Munich, the Research Director of the Helmholtz Diabetes Center, and the Chair of the Division of Metabolic Diseases at the Technical University Munich, Germany. The aim of his Institute is the discovery, validation and targeting of novel pathomechanisms and molecular signals in metabolic disease. To this end, his research is focused on identifying molecular signals for the development of personalized preventative and therapeutic strategies for diabetes mellitus and obesity, as well as related comorbidities.

  • Chun-Xia Yi

    Dr Chun-Xia Yi received an MD from Tongji Medical College of Huazhong University of Science and Technology, China, and a PhD from the Netherlands Institute for Neuroscience. She is a group leader in the Institute for Diabetes and Obesity, Helmholtz Zentrum München, Germany, and an Assistant Professor in the Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Netherlands. Her research focuses on deconstructing neuron–microglia circuits in the brain regions that sense energy states and regulate metabolism, in animal models and humans. She aims to identify targets for normalizing dysfunctional microglia in metabolic diseases.

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