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.

Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism

Abstract

Astrocytes, microglia, and tanycytes play active roles in the regulation of hypothalamic feeding circuits. These non-neuronal cells are crucial in determining the functional interactions of specific neuronal subpopulations involved in the control of metabolism. Recent advances in biology, optics, genetics, and pharmacology have resulted in the emergence of novel and highly sophisticated approaches for studying hypothalamic neuronal–glial networks. Here we summarize the progress in the field and argue that glial–neuronal interactions provide a core hub integrating food-related cues, interoceptive signals, and internal states to adapt a complex set of physiological responses operating on different timescales to finely tune behavior and metabolism according to metabolic status. This expanding knowledge helps to redefine our understanding of the physiology of food intake and energy metabolism.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The cellular functional heterogeneity of hypothalamic AgRP or NPY and POMC neurons in metabolic sensing and systemic metabolism.
Fig. 2: The cellular functional heterogeneity of hypothalamic non-neuronal cells in metabolic sensing and systemic metabolism.

References

  1. 1.

    Bruch, H. The Fröhlich syndrome: report of the original case. 1939. Obes. Res. 1, 329–331 (1993).

    CAS  PubMed  Google Scholar 

  2. 2.

    Hetherington, A. W. Non-production of hypothalamic obesity in the rat by lesions rostral or dorsal to the ventro-medial hypothalamic nuclei. J. Comp. Neurol. 80, 33–45 (1944).

    Google Scholar 

  3. 3.

    Brobeck, J. R. Mechanism of the development of obesity in animals with hypothalamic lesions. Physiol. Rev. 26, 541–559 (1946).

    CAS  PubMed  Google Scholar 

  4. 4.

    Hetherington, A. W. & Ranson, S. W. The relation of various hypothalamic lesions to adiposity in the rat. J. Comp. Neurol. 76, 475–499 (1942).

    Google Scholar 

  5. 5.

    Anand, B. K. & Brobeck, J. R. Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med. 24, 123–140 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

    CAS  PubMed  Google Scholar 

  7. 7.

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  PubMed  Google Scholar 

  8. 8.

    Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

    CAS  PubMed  Google Scholar 

  9. 9.

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

    CAS  PubMed  Google Scholar 

  10. 10.

    Coleman, D. L. Diabetes-obesity syndromes in mice. Diabetes 31 Suppl 1 Pt 2, 1–6 (1982).

    CAS  PubMed  Google Scholar 

  11. 11.

    Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).

    CAS  PubMed  Google Scholar 

  12. 12.

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

    CAS  PubMed  Google Scholar 

  13. 13.

    Djogo, T. et al. Adult NG2-glia are required for median eminence-mediated leptin sensing and body weight control. Cell Metab. 23, 797–810 (2016).

    CAS  PubMed  Google Scholar 

  14. 14.

    Tatemoto, K., Carlquist, M. & Mutt, V. Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296, 659–660 (1982).

    CAS  PubMed  Google Scholar 

  15. 15.

    Miltenberger, R. J., Mynatt, R. L., Wilkinson, J. E. & Woychik, R. P. The role of the agouti gene in the yellow obese syndrome. J. Nutr. 127, 1902S–1907S (1997).

    CAS  PubMed  Google Scholar 

  16. 16.

    Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246–8250 (1993).

    CAS  PubMed  Google Scholar 

  17. 17.

    Xu, A. W. et al. Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol. 3, e415 (2005).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wu, Q., Howell, M. P., Cowley, M. A. & Palmiter, R. D. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc. Natl Acad. Sci. USA 105, 2687–2692 (2008).

    CAS  PubMed  Google Scholar 

  20. 20.

    Dietrich, M. O., Zimmer, M. R., Bober, J. & Horvath, T. L. Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160, 1222–1232 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Padilla, S. L. et al. Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat. Neurosci. 19, 734–741 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Chen, Y., Lin, Y. C., Kuo, T. W. & Knight, Z. A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841 (2015).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Betley, J. N., Cao, Z. F., Ritola, K. D. & Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Steculorum, S. M. et al. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Wu, Q., Boyle, M. P. & Palmiter, R. D. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Joly-Amado, A. et al. Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. 31, 4276–4288 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Matarese, G. et al. Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc. Natl Acad. Sci. USA 110, 6193–6198 (2013).

    CAS  PubMed  Google Scholar 

  29. 29.

    Kim, J. G. et al. AgRP neurons regulate bone mass. Cell Rep. 13, 8–14 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).

    CAS  PubMed  Google Scholar 

  31. 31.

    Varela, L. & Horvath, T. L. AgRP neurons: a switch between peripheral carbohydrate and lipid utilization. EMBO J. 31, 4252–4254 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Diano, S. et al. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat. Med. 17, 1121–1127 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Toda, C., Santoro, A., Kim, J. D. & Diano, S. POMC neurons: from birth to death. Annu. Rev. Physiol. 79, 209–236 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Romanov, R. A. et al. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat. Neurosci. 20, 176–188 (2017).

    CAS  PubMed  Google Scholar 

  37. 37.

    Fenselau, H. et al. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

    Zhang, X. & van den Pol, A. N. Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat. Neurosci. 19, 1341–1347 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Fitzgerald, P. & Dinan, T. G. Prolactin and dopamine: what is the connection? A review article. J. Psychopharmacol. 22 Suppl, 12–19 (2008).

    PubMed  Google Scholar 

  40. 40.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Horvath, T. L., Diano, S. & van den Pol, A. N. Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J. Neurosci. 19, 1072–1087 (1999).

    CAS  PubMed  Google Scholar 

  42. 42.

    Horvath, T. L. et al. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J. Comp. Neurol. 415, 145–159 (1999).

    CAS  PubMed  Google Scholar 

  43. 43.

    Nieh, E. H. et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    King, B. M. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol. Behav. 87, 221–244 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Choi, Y. H., Fujikawa, T., Lee, J., Reuter, A. & Kim, K. W. Revisiting the ventral medial nucleus of the hypothalamus: the roles of SF-1 neurons in energy homeostasis. Front. Neurosci. 7, 71 (2013).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

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

    CAS  PubMed  Google Scholar 

  47. 47.

    Oberheim, N. A., Goldman, S. A. & Nedergaard, M. Heterogeneity of astrocytic form and function. Methods Mol. Biol. 814, 23–45 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018).

    PubMed  Google Scholar 

  49. 49.

    Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    CAS  PubMed  Google Scholar 

  51. 51.

    Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Verkhratsky, A., Orkand, R. K. & Kettenmann, H. Glial calcium: homeostasis and signaling function. Physiol. Rev. 78, 99–141 (1998).

    CAS  PubMed  Google Scholar 

  53. 53.

    Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).

    CAS  PubMed  Google Scholar 

  54. 54.

    Clasadonte, J., Scemes, E., Wang, Z., Boison, D. & Haydon, P. G. Connexin 43-mediated astroglial metabolic networks contribute to the regulation of the sleep-wake cycle. Neuron 95, 1365–1380.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    García-Cáceres, C. et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166, 867–880 (2016).

    PubMed  Google Scholar 

  56. 56.

    Kim, J. G. et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908–910 (2014).

    CAS  PubMed  Google Scholar 

  57. 57.

    Allard, C. et al. Hypothalamic astroglial connexins are required for brain glucose sensing-induced insulin secretion. J. Cereb. Blood Flow Metab. 34, 339–346 (2014).

    CAS  PubMed  Google Scholar 

  58. 58.

    Chari, M. et al. Glucose transporter-1 in the hypothalamic glial cells mediates glucose sensing to regulate glucose production in vivo. Diabetes 60, 1901–1906 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Schipper, H. M. Gomori-positive astrocytes: biological properties and implications for neurologic and neuroendocrine disorders. Glia 4, 365–377 (1991).

    CAS  PubMed  Google Scholar 

  60. 60.

    Young, J. K. & McKenzie, J. C. GLUT2 immunoreactivity in Gomori-positive astrocytes of the hypothalamus. J. Histochem. Cytochem. 52, 1519–1524 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Chowen, J. A. et al. The role of astrocytes in the hypothalamic response and adaptation to metabolic signals. Prog. Neurobiol. 144, 68–87 (2016).

    PubMed  Google Scholar 

  62. 62.

    Tasker, J. G., Oliet, S. H., Bains, J. S., Brown, C. H. & Stern, J. E. Glial regulation of neuronal function: from synapse to systems physiology. J. Neuroendocrinol. 24, 566–576 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gordon, G. R. et al. Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat. Neurosci. 8, 1078–1086 (2005).

    CAS  PubMed  Google Scholar 

  64. 64.

    Gordon, G. R. et al. Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses. Neuron 64, 391–403 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Yang, L., Qi, Y. & Yang, Y. Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep. 11, 798–807 (2015).

    CAS  PubMed  Google Scholar 

  66. 66.

    Prevot, V. et al. The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. Endocr. Rev. 39, 333–368 (2018).

    PubMed  Google Scholar 

  67. 67.

    Clasadonte, J. & Prevot, V. The special relationship: glia-neuron interactions in the neuroendocrine hypothalamus. Nat. Rev. Endocrinol. 14, 25–44 (2018).

    CAS  PubMed  Google Scholar 

  68. 68.

    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, 607–617 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Schaeffer, M. et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc. Natl Acad. Sci. USA 110, 1512–1517 (2013).

    CAS  PubMed  Google Scholar 

  70. 70.

    Banks, W. A., DiPalma, C. R. & Farrell, C. L. Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 20, 1341–1345 (1999).

    CAS  PubMed  Google Scholar 

  71. 71.

    Balland, E. et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19, 293–301 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Collden, G. et al. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Mol. Metab. 4, 15–24 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Kettenmann, H., Kirchhoff, F. & Verkhratsky, A. Microglia: new roles for the synaptic stripper. Neuron 77, 10–18 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Gao, Y. et al. Deficiency of leptin receptor in myeloid cells disrupts hypothalamic metabolic circuits and causes body weight increase. Mol. Metab. 7, 155–160 (2018).

    CAS  PubMed  Google Scholar 

  75. 75.

    Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

    CAS  PubMed  Google Scholar 

  76. 76.

    Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    CAS  PubMed  Google Scholar 

  77. 77.

    Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Gao, Y. et al. Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62, 17–25 (2014).

    PubMed  Google Scholar 

  79. 79.

    Jin, S. et al. Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Sci. Rep. 6, 29424 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Schneeberger, M. et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172–187 (2013).

    CAS  PubMed  Google Scholar 

  81. 81.

    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, 14875–14880 (2010).

    CAS  PubMed  Google Scholar 

  82. 82.

    Stoeckel, L. E. et al. Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage 41, 636–647 (2008).

    PubMed  Google Scholar 

  83. 83.

    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, 359–370 (2009).

    CAS  PubMed  Google Scholar 

  84. 84.

    Gao, Y. et al. Dietary sugars, not lipids, drive hypothalamic inflammation. Mol. Metab. 6, 897–908 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Kuno, R. et al. Autocrine activation of microglia by tumor necrosis factor-alpha. J. Neuroimmunol. 162, 89–96 (2005).

    CAS  PubMed  Google Scholar 

  86. 86.

    Yi, C. X. et al. TNFα drives mitochondrial stress in POMC neurons in obesity. Nat. Commun. 8, 15143 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Fuente-Martín, E. et al. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J. Clin. Invest. 122, 3900–3913 (2012).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Gao, Y. et al. Disruption of lipid uptake in astroglia exacerbates diet-induced obesity. Diabetes 66, 2555–2563 (2017).

    CAS  PubMed  Google Scholar 

  89. 89.

    Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  90. 90.

    Balland, E. & Cowley, M. A. Short-term high-fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity. J. Neuroendocrinol. https://doi.org/10.1111/jne.12504 (2017).

    Article  PubMed  Google Scholar 

  91. 91.

    Caro, J. F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).

    CAS  PubMed  Google Scholar 

  92. 92.

    Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2, 589–593 (1996).

    CAS  PubMed  Google Scholar 

  93. 93.

    Yi, C. X. et al. High calorie diet triggers hypothalamic angiopathy. Mol. Metab. 1, 95–100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    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, 686–690 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat. Rev. Neurosci. 10, 647–658 (2009).

    CAS  PubMed  Google Scholar 

  96. 96.

    Dietrich, M. O. & Horvath, T. L. Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci. 36, 65–73 (2013).

    CAS  PubMed  Google Scholar 

  97. 97.

    Cristino, L. et al. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc. Natl Acad. Sci. USA 110, E2229–E2238 (2013).

    CAS  PubMed  Google Scholar 

  98. 98.

    Woods, S. C., Seeley, R. J., Porte, D. Jr. & Schwartz, M. W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

    CAS  PubMed  Google Scholar 

  99. 99.

    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 

  100. 100.

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

    CAS  PubMed  Google Scholar 

  101. 101.

    Koch, M. & Horvath, T. L. Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism. Mol. Psychiatry 19, 752–761 (2014).

    CAS  PubMed  Google Scholar 

  102. 102.

    Harris, G. C., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005).

    CAS  PubMed  Google Scholar 

  103. 103.

    Castro, D. C. & Berridge, K. C. Advances in the neurobiological bases for food ‘liking’ versus ‘wanting’. Physiol. Behav. 136, 22–30 (2014).

    CAS  PubMed  Google Scholar 

  104. 104.

    Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006).

    CAS  PubMed  Google Scholar 

  105. 105.

    Figlewicz, D. P. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat: historical perspective. Brain Res. 1645, 68–70 (2016).

    CAS  PubMed  Google Scholar 

  106. 106.

    Abizaid, A. et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229–3239 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Woods, S. C. & Begg, D. P. Food for thought: revisiting the complexity of food intake. Cell Metab. 22, 348–351 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Davidson, T. L. et al. Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation. Hippocampus 19, 235–252 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Diano, S. et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat. Neurosci. 9, 381–388 (2006).

    CAS  PubMed  Google Scholar 

  110. 110.

    Lathe, R. Hormones and the hippocampus. J. Endocrinol. 169, 205–231 (2001).

    CAS  PubMed  Google Scholar 

  111. 111.

    Carus-Cadavieco, M. et al. Gamma oscillations organize top-down signalling to hypothalamus and enable food seeking. Nature 542, 232–236 (2017).

    CAS  PubMed  Google Scholar 

  112. 112.

    Mandelblat-Cerf, Y. et al. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. eLife 4, e07122 (2015).

    PubMed Central  Google Scholar 

  113. 113.

    Baufeld, C., Osterloh, A., Prokop, S., Miller, K. R. & Heppner, F. L. High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol. 132, 361–375 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    André, C. et al. Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation. Diabetes 66, 908–919 (2017).

    PubMed  Google Scholar 

  115. 115.

    Valdearcos, M. et al. Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 26, 185–197.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Lee, C. H. et al. Hypothalamic macrophage inducible nitric oxide synthase mediates obesity-associated hypothalamic inflammation. Cell Rep. 25, 934–946.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Zhang, Y., Reichel, J. M., Han, C., Zuniga-Hertz, J. P. & Cai, D. Astrocytic process plasticity and IKKβ/NF-κB in central control of blood glucose, blood pressure, and body weight. Cell Metab. 25, 1091–1102.e4 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Douglass, J. D., Dorfman, M. D., Fasnacht, R., Shaffer, L. D. & Thaler, J. P. Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol. Metab. 6, 366–373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by European Research Council ERC AdG (HypoFlam no. 695054) to M.H.T. and ERC STG (AstroNeuroCrosstalk no. 757393) to C.G.-C.; ANR/DFG Nutripathos Project ANR-15-CE14-0030-01/02 to M.H.T. and S.L.; the Deutsche Forschungsgemeinschaft (SFB 1052) Obesity Mechanisms to M.K. and I.B.; and the Agence National pour la Recherche (ANR) grant number ANR-15-CE14-0025 to V.P. and ANR-15-CE14-0030-01 and ANR-16-CE14-0026-02 to S.L.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Matthias H. Tschöp.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

García-Cáceres, C., Balland, E., Prevot, V. et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci 22, 7–14 (2019). https://doi.org/10.1038/s41593-018-0286-y

Download citation

Further reading

Search

Quick links