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Hypothalamic innate immune reaction in obesity

Key Points

  • Hypothalamic metabolic sensing requires an interactive network of neurons, glial cells and vasculature to enable appropriate integration of complex metabolic feedback signals

  • Exposure to hypercaloric environments induces inflammatory-like responses not only in peripheral tissues but also in the central nervous system, especially in the hypothalamus

  • The term 'hypothalamic inflammation' is being used more and more frequently to describe a complex of hypothalamic processes that occurs in response to hypercaloric diets

  • The phenomenon of hypothalamic inflammation in obesity is more similar to an innate immune reaction than to conventionally defined inflammation

  • To address the hypothalamic innate immune reaction therapeutically, cell-specific strategies should be developed that enable prevention of the adverse effects of systemic treatment approaches

Abstract

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.

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Figure 1: The cytoarchitecture of hypothalamic NPY and POMC neurons, microglia, astrocytes and vasculature.
Figure 2: The diversity of hypothalamic microglia and macrophages visualized in CX3Cr1-GFP mice.
Figure 3: Morphological comparison of microglial reactivity in diet-induced obesity as visualized by AIF-1-ir.
Figure 4: The distribution pattern of the GFP+ astrocytes (green) and GFAP-ir astrocytes (red) in hGFAP-GFP transgenic mouse hypothalamus.
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.

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Acknowledgements

F.L.H. is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR 43, NeuroCure Exc 257 and HE 3130/6-1), the Federal Ministry of Education and Research (DLR/BMBF; Kompetenznetz Degenerative Demenzen) and by a collaborative research grant of the Berlin Institute of Health (BIH). I.B. is supported by the Deutsche Forschungsgemeinsschaft (FOR 1336 and SFB 1052), ICEMED and DZD. M.H.T. is supported by the Alexander von Humboldt Foundation, the Deutsches Zentrum für Diabetesforschung (DZD), and the Helmholtz Alliance ICEMED–Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association.

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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.

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Correspondence to Matthias H. Tschöp.

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Kälin, S., Heppner, F., Bechmann, I. et al. Hypothalamic innate immune reaction in obesity. Nat Rev Endocrinol 11, 339–351 (2015). https://doi.org/10.1038/nrendo.2015.48

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