Abstract
Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory response. Increasing evidence has highlighted a critical role of astrocytes in the effects of leptin on the hypothalamus. In addition, astrocytes participate in neuroinflammation by producing and releasing a wide range of inflammatory mediators. In this study, we aimed to investigate the age-dependent effect of leptin on pro- and anti-inflammatory cytokines released by the hypothalamic astrocyte cultures obtained from newborn, adult, and aged Wistar rats. In hypothalamic astrocytes from newborn rats, leptin did not change the release of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). On the other contrary, leptin increased the release of both TNF-α and IL-1β in astrocyte cultures from adult and aged animals. Regarding the anti-inflammatory cytokine interleukin 10 (IL-10), we did not observe any change in response to leptin. In conclusion, our data suggests a pro-inflammatory action of leptin on the hypothalamus during aging. This in turn may be related to the triggering of metabolic disorders, as both of these conditions are associated with neuroinflammation.
This is a preview of subscription content, log in via an institution to check access.
References
Abella V, Scotece M, Conde J et al (2017) Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 13:100–109. https://doi.org/10.1038/nrrheum.2016.209
Allison MB, Myers MG (2014) Connecting leptin signaling to biological function. J Endocrinol 223:T25–T35. https://doi.org/10.1530/JOE-14-0404
Bélanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738. https://doi.org/10.1016/j.cmet.2011.08.016
Cheunsuang O, Morris R (2005) Astrocytes in the arcuate nucleus and median eminence that take up a fluorescent dye from the circulation express leptin receptors and neuropeptide Y Y1 receptors. Glia 52:228–233. https://doi.org/10.1002/glia.20239
Fuente-Martín E, García-Cáceres C, Granado M et al (2012) Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J Clin Invest 122:3900–3913. https://doi.org/10.1172/JCI64102
Gainsford T, Willson TA, Metcalf D et al (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A 93:14564–14568
Garcia JM, Stillings SA, Leclerc JL et al (2017) Role of Interleukin-10 in acute brain injuries. Front Neurol 8:244. https://doi.org/10.3389/fneur.2017.00244
García-Cáceres C, Fuente-Martín E, Burgos-Ramos E et al (2011) Differential acute and chronic effects of leptin on hypothalamic astrocyte morphology and synaptic protein levels. Endocrinology 152:1809–1818. https://doi.org/10.1210/en.2010-1252
Gupta S, Agrawal S, Gollapudi S (2013) Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans. Immun Ageing A 10:3. https://doi.org/10.1186/1742-4933-10-3
He ML, Lv ZY, Shi X et al (2017) Interleukin-10 release from astrocytes suppresses neuronal apoptosis via the TLR2/NFκB pathway in a neonatal rat model of hypoxic-ischemic brain damage. J Neurochem. https://doi.org/10.1111/jnc.14126
Holmin S, Mathiesen T (2000) Intracerebral administration of interleukin-1beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg 92:108–120. https://doi.org/10.3171/jns.2000.92.1.0108
Jensen CJ, Massie A, De Keyser J (2013) Immune players in the CNS: the astrocyte. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 8:824–839. https://doi.org/10.1007/s11481-013-9480-6
Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell 13:1059–1067. https://doi.org/10.1111/acel.12268
Kälin S, Heppner FL, Bechmann I et al (2015) Hypothalamic innate immune reaction in obesity. Nat Rev Endocrinol 11:339–351. https://doi.org/10.1038/nrendo.2015.48
Kim JG, Suyama S, Koch M et al (2014) Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17:908–910. https://doi.org/10.1038/nn.3725
Koga S, Kojima A, Ishikawa C et al (2014) Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression. Neurobiol Dis 71:180–192. https://doi.org/10.1016/j.nbd.2014.08.015
Ma XH, Muzumdar R, Yang XM et al (2002) Aging is associated with resistance to effects of leptin on fat distribution and insulin action. J Gerontol A Biol Sci Med Sci 57:B225–B231
Morselli E, Fuente-Martin E, Finan B et al (2014) Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα. Cell Rep 9:633–645. https://doi.org/10.1016/j.celrep.2014.09.025
Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431. https://doi.org/10.1016/j.tins.2009.05.001
Pinteaux E, Inoue W, Schmidt L et al (2007) Leptin induces interleukin-1beta release from rat microglial cells through a caspase 1 independent mechanism. J Neurochem 102:826–833. https://doi.org/10.1111/j.1471-4159.2007.04559.x
Rostás I, Tenk J, Mikó A et al (2016) Age-related changes in acute central leptin effects on energy balance are promoted by obesity. Exp Gerontol 85:118–127. https://doi.org/10.1016/j.exger.2016.10.006
Rottkamp DM, Rudenko IA, Maier MT et al (2015) Leptin potentiates astrogenesis in the developing hypothalamus. Mol Metab 4:881–889. https://doi.org/10.1016/j.molmet.2015.08.005
Santos CL, Roppa PHA, Truccolo P et al (2018) Age-dependent neurochemical remodeling of hypothalamic astrocytes. Mol Neurobiol 55:5565–5579. https://doi.org/10.1007/s12035-017-0786-x
Strle K, Zhou JH, Shen WH et al (2001) Interleukin-10 in the brain. Crit Rev Immunol 21:427–449
Suzukawa M, Nagase H, Ogahara I et al (2011) Leptin enhances survival and induces migration, degranulation, and cytokine synthesis of human basophils. J Immunol Baltim Md 1950 186:5254–5260. https://doi.org/10.4049/jimmunol.1004054
Valdearcos M, Xu AW, Koliwad SK (2015) Hypothalamic inflammation in the control of metabolic function. Annu Rev Physiol 77:131–160. https://doi.org/10.1146/annurev-physiol-021014-071656
Wang Y, Hsuchou H, He Y et al (2015) Role of astrocytes in leptin signaling. J Mol Neurosci MN 56:829–839. https://doi.org/10.1007/s12031-015-0518-5
Wohleb ES, Godbout JP (2013) Basic aspects of the immunology of neuroinflammation. Mod Trends Pharmacopsychiatry 28:1–19. https://doi.org/10.1159/000343964
Zarkesh-Esfahani H, Pockley G, Metcalfe RA et al (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol Baltim Md 1950 167:4593–4599
Zhang G, Li J, Purkayastha S et al (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497:211–216. https://doi.org/10.1038/nature12143
Acknowledgments
This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Universidade Federal do Rio Grande do Sul, and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN/CNPq).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Santos, C.L., Bobermin, L.D., Souza, D.O. et al. Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats. Metab Brain Dis 33, 2059–2063 (2018). https://doi.org/10.1007/s11011-018-0311-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-018-0311-6