Journal
CELL METABOLISM
Volume 26, Issue 1, Pages 185-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2017.05.015
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Funding
- American Diabetes Association (Pathway Award) [1-14-ACE-51]
- NIDDK [K08 DK088872, T32 DK7247-37, F32 DK108473-01, R01 DK103175-02]
- UCSF Diabetes Family Fund Award
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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-kappa B-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-kappa B 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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