Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility

Publication date: 5 July 2017
Source:Cell Metabolism, Volume 26, Issue 1
Author(s): Martin Valdearcos, John D. Douglass, Megan M. Robblee, Mauricio D. Dorfman, Daniel R. Stifler, Mariko L. Bennett, Irene Gerritse, Rachael Fasnacht, Ben A. Barres, Joshua P. Thaler, Suneil K. Koliwad
Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

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Teaser

Whether the hypothalamic accumulation of activated microglia is a cause or a consequence of weight gain has been unclear. Valdearcos et al. show that microglia orchestrate a complex hypothalamic immune response to dietary excess and that microglial inflammatory signaling regulates both energy intake and expenditure; these cells and their signaling pathways could be targeted in obesity.


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