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Cellular Contributors to Hypothalamic Inflammation in Obesity

  • Lee, Chan Hee (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Suk, Kyoungho (Department of Pharmacology, School of Medicine, Kyungpook National University College of Medicine) ;
  • Yu, Rina (Department of Food Science and Nutrition, University of Ulsan) ;
  • Kim, Min-Seon (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2020.03.02
  • Accepted : 2020.04.20
  • Published : 2020.05.31

Abstract

The hypothalamus is a crucial organ for the maintenance of appropriate body fat storage. Neurons in the hypothalamic arcuate nucleus (ARH) detect energy shortage or surplus via the circulating concentrations of metabolic hormones and nutrients, and then coordinate energy intake and expenditure to maintain energy homeostasis. Malfunction or loss of hypothalamic ARH neurons results in obesity. Accumulated evidence suggests that hypothalamic inflammation is a key pathological mechanism that links chronic overconsumption of a high-fat diet (HFD) with the development of obesity and related metabolic complications. Interestingly, overnutrition-induced hypothalamic inflammation occurs specifically in the ARH, where microglia initiate an inflammatory response by releasing proinflammatory cytokines and chemokines in response to excessive fatty acid flux. Upon more prolonged HFD consumption, astrocytes and perivascular macrophages become involved and sustain hypothalamic inflammation. ARH neurons are victims of hypothalamic inflammation, but they may actively participate in hypothalamic inflammation by sending quiescence or stress signals to surrounding glia. In this mini-review, we describe the current state of knowledge regarding the contributions of neurons and glia, and their interactions, to HFD-induced hypothalamic inflammation.

Keywords

References

  1. Abbott, N.J., Ronnback, L., and Hansson, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41-53. https://doi.org/10.1038/nrn1824
  2. Allan, S.M., Harrison, D.C., Read, S., Collins, B., Parsons, A.A., Philpott, K., and Rothwell, N.J. (2001). Selective increases in cytokine expression in the rat brain in response to striatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and interleukin-1. Brain Res. Mol. Brain Res. 93, 180-189. https://doi.org/10.1016/S0169-328X(01)00211-X
  3. Allen, A.R., Eilertson, K., Sharma, S., Schneider, D., Baure, J., Allen, B., Rosi, S., Raber, J., and Fike, J.R. (2013). Effects of radiation combined injury on hippocampal function are modulated in mice deficient in chemokine receptor 2 (CCR2). Radiat. Res. 180, 78-88. https://doi.org/10.1667/RR3344.1
  4. Argaw, A.T., Asp, L., Zhang, J., Navrazhina, K., Pham, T., Mariani, J.N., Mahase, S., Dutta, D.J., Seto, J., Kramer, E.G., et al. (2012). Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454-2468. https://doi.org/10.1172/JCI60842
  5. Benarroch, E.E. (2005). Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc. 80, 1326-1338. https://doi.org/10.4065/80.10.1326
  6. Biber, K., Neumann, H., Inoue, K., and Boddeke, H.W. (2007). Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci. 30, 596-602. https://doi.org/10.1016/j.tins.2007.08.007
  7. Cai, D. and Liu, T. (2011). Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann. N. Y. Acad. Sci. 1243, E1-E39. https://doi.org/10.1111/j.1749-6632.2011.06388.x
  8. Cardona, A.E., Pioro, E.P., Sasse, M.E., Kostenko, V., Cardona, S.M., Dijkstra, I.M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006). Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917-924. https://doi.org/10.1038/nn1715
  9. De Souza, C.T., Araujo, E.P., Bordin, S., Ashimine, R., Zollner, R.L., Boschero, A.C., Saad, M.J., and Velloso, L.A. (2005). Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146, 4192-4199. https://doi.org/10.1210/en.2004-1520
  10. Dorfman, M.D., Krull, J.E., Douglass, J.D., Fasnacht, R., Lara-Lince, F., Meek, T.H., Shi, X., Damian, V., Nguyen, H.T., Matsen, M.E., et al. (2017). Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice. Nat. Commun. 8, 14556. https://doi.org/10.1038/ncomms14556
  11. Douglass, J.D., Dorfman, M.D., Fasnacht, R., Shaffer, L.D., and Thaler, J.P. (2017). Astrocyte IKKbeta/NF-kappaB signaling is required for dietinduced obesity and hypothalamic inflammation. Mol. Metab. 6, 366-373. https://doi.org/10.1016/j.molmet.2017.01.010
  12. Gao, Y., Ottaway, N., Schriever, S.C., Legutko, B., Garcia-Caceres, C., de la Fuente, E., Mergen, C., Bour, S., Thaler, J.P., Seeley, R.J., et al. (2014). Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62, 17-25. https://doi.org/10.1002/glia.22580
  13. Horvath, T.L., Sarman, B., Garcia-Caceres, C., Enriori, P.J., Sotonyi, P., Shanabrough, M., Borok, E., Argente, J., Chowen, J.A., Perez-Tilve, D., et al. (2010). Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc. Natl. Acad. Sci. U. S. A. 107, 14875-14880. https://doi.org/10.1073/pnas.1004282107
  14. Ioannou, M.S., Jackson, J., Sheu, S.H., Chang, C.L., Weigel, A.V., Liu, H., Pasolli, H.A., Xu, C.S., Pang, S., Matthies, D., et al. (2019). Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522-1535.e14. https://doi.org/10.1016/j.cell.2019.04.001
  15. Jais, A. and Brüning, J.C. (2017). Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Invest. 127, 24-32. https://doi.org/10.1172/JCI88878
  16. Jha, M.K., Jo, M., Kim, J.H., and Suk, K. (2019). Microglia-astrocyte crosstalk: an intimate molecular conversation. Neuroscientist 25, 227-240. https://doi.org/10.1177/1073858418783959
  17. Jung, C.H. and Kim, M.S. (2013). Molecular mechanisms of central leptin resistance in obesity. Arch. Pharm. Res. 36, 201-207. https://doi.org/10.1007/s12272-013-0020-y
  18. Kierdorf, K. and Prinz, M. (2017). Microglia in steady state. J. Clin. Invest. 127, 3201-3209. https://doi.org/10.1172/JCI90602
  19. Kim, J., Kwon, Y.H., Kim, C.S., Tu, T.H., Kim, B.S., Joe, Y., Chung, H.T., Goto, T., Kawada, T., Park, T., et al. (2018). The involvement of 4-1BB/4-1BBL signaling in glial cell-mediated hypothalamic inflammation in obesity. FEBS Open Bio 8, 843-853. https://doi.org/10.1002/2211-5463.12426
  20. Kirchhoff, F., Dringen, R., and Giaume, C. (2001). Pathways of neuronastrocyte interactions and their possible role in neuroprotection. Eur. Arch. Psychiatry Clin. Neurosci. 251, 159-169. https://doi.org/10.1007/s004060170036
  21. Kwon, Y.H., Kim, J., Kim, C.S., Tu, T.H., Kim, M.S., Suk, K., Kim, D.H., Lee, B.J., Choi, H.S., Park, T., et al. (2017). Hypothalamic lipid-laden astrocytes induce microglia migration and activation. FEBS Lett. 591, 1742-1751. https://doi.org/10.1002/1873-3468.12691
  22. Langlet, F., Levin, B.E., Luquet, S., Mazzone, M., Messina, A., Dunn-Meynell, A.A., Balland, E., Lacombe, A., Mazur, D., Carmeliet, P., et al. (2013). 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. https://doi.org/10.1016/j.cmet.2013.03.004
  23. Lee, C.H., Kim, H.J., Lee, Y.S., Kang, G.M., Lim, H.S., Lee, S.H., Song, D.K., Kwon, O., Hwang, I., Son, M., et al. (2018). Hypothalamic macrophage inducible nitric oxide synthase mediates obesity-associated hypothalamic inflammation. Cell Rep. 25, 934-946.e5. https://doi.org/10.1016/j.celrep.2018.09.070
  24. Lee, C.H., Shin, S.H., Kang, G.M., Kim, S., Kim, J., Yu, R., and Kim, M.S. (2019). Cellular source of hypothalamic macrophage accumulation in dietinduced obesity. J. Neuroinflammation 16, 221. https://doi.org/10.1186/s12974-019-1607-0
  25. Liddelow, S.A., Guttenplan, K.A., Clarke, L.E., Bennett, F.C., Bohlen, C.J., Schirmer, L., Bennett, M.L., Munch, A.E., Chung, W.S., Peterson, T.C., et al. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481-487. https://doi.org/10.1038/nature21029
  26. Lumeng, C.N. and Saltiel, A.R. (2011). Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111-2117. https://doi.org/10.1172/JCI57132
  27. Mizuno, T. (2015). Neuron-microglia interactions in neuroinflammation. Clin. Exp. Neuroimmunol. 6, 225-231. https://doi.org/10.1111/cen3.12228
  28. Moraes, J.C., Coope, A., Morari, J., Cintra, D.E., Roman, E.A., Pauli, J.R., Romanatto, T., Carvalheira, J.B., Oliveira, A.L., Saad, M.J., et al. (2009). Highfat diet induces apoptosis of hypothalamic neurons. PLoS One 4, e5045. https://doi.org/10.1371/journal.pone.0005045
  29. Nakagawa, S., Izumi, Y., Takada-Takatori, Y., Akaike, A., and Kume, T. (2019). Increased CCL6 expression in astrocytes and neuronal protection from neuron-astrocyte interactions. Biochem. Biophys. Res. Commun. 519, 777-782. https://doi.org/10.1016/j.bbrc.2019.09.030
  30. Paolicelli, R.C., Bisht, K., and Tremblay, M.E. (2014). Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Front. Cell. Neurosci. 8, 129. https://doi.org/10.3389/fncel.2014.00129
  31. Park, J., Joe, Y., Ryter, S.W., Surh, Y.J., and Chung, H.T. (2019). Similarities and distinctions in the effects of metformin and carbon monoxide in immunometabolism. Mol. Cells. 42, 292-300.
  32. Poon, K., Barson, J.R., Ho, H.T., and Leibowitz, S.F. (2016). Relationship of the chemokine, CXCL12, to effects of dietary fat on feeding-related behaviors and hypothalamic neuropeptide systems. Front. Behav. Neurosci. 10, 51.
  33. Ricci, G., Volpi, L., Pasquali, L., Petrozzi, L., and Siciliano, G. (2009). Astrocyte-neuron interactions in neurological disorders. J. Biol. Phys. 35, 317-336. https://doi.org/10.1007/s10867-009-9157-9
  34. Roh, E., Song, D.K., and Kim, M.S. (2016). Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp. Mol. Med. 48, e216. https://doi.org/10.1038/emm.2016.4
  35. Schwartz, M.W. (2006). Central nervous system regulation of food intake. Obesity (Silver Spring) 14 Suppl 1, 1s-8s. https://doi.org/10.1038/oby.2006.275
  36. Serrats, J., Schiltz, J.C., Garcia-Bueno, B., van Rooijen, N., Reyes, T.M., and Sawchenko, P.E. (2010). Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94-106. https://doi.org/10.1016/j.neuron.2009.11.032
  37. Shao, Z. and Schwarz, H. (2011). CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J. Leukoc. Biol. 89, 21-29. https://doi.org/10.1189/jlb.0510315
  38. Szepesi, Z., Manouchehrian, O., Bachiller, S., and Deierborg, T. (2018). Bidirectional microglia-neuron communication in health and disease. Front. Cell. Neurosci. 12, 323. https://doi.org/10.3389/fncel.2018.00323
  39. Thaler, J.P., Yi, C.X., Schur, E.A., Guyenet, S.J., Hwang, B.H., Dietrich, M.O., Zhao, X., Sarruf, D.A., Izgur, V., Maravilla, K.R., et al. (2012). Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153-162. https://doi.org/10.1172/JCI59660
  40. Tian, D.S., Peng, J., Murugan, M., Feng, L.J., Liu, J.L., Eyo, U.B., Zhou, L.J., Mogilevsky, R., Wang, W., and Wu, L.J. (2017). Chemokine CCL2-CCR2 signaling induces neuronal cell death via STAT3 activation and IL-1beta production after status epilepticus. J. Neurosci. 37, 7878-7892. https://doi.org/10.1523/JNEUROSCI.0315-17.2017
  41. Valdearcos, M., Douglass, J.D., Robblee, M.M., Dorfman, M.D., Stifler, D.R., Bennett, M.L., Gerritse, I., Fasnacht, R., Barres, B.A., Thaler, J.P., et al. (2017). Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 26, 185-197.e3. https://doi.org/10.1016/j.cmet.2017.05.015
  42. Valdearcos, M., Robblee, M.M., Benjamin, D.I., Nomura, D.K., Xu, A.W., and Koliwad, S.K. (2014). Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep. 9, 2124-2138. https://doi.org/10.1016/j.celrep.2014.11.018
  43. Verkhratsky, A. and Nedergaard, M. (2018). Physiology of astroglia. Physiol. Rev. 98, 239-389. https://doi.org/10.1152/physrev.00042.2016
  44. Williams, K., Alvarez, X., and Lackner, A.A. (2001). Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36, 156-164. https://doi.org/10.1002/glia.1105
  45. Zhang, Y., Reichel, J.M., Han, C., Zuniga-Hertz, J.P., and Cai, D. (2017). Astrocytic process plasticity and IKKbeta/NF-kappaB in central control of blood glucose, blood pressure, and body weight. Cell Metab. 25, 1091-1102.e4. https://doi.org/10.1016/j.cmet.2017.04.002

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