Hormones and diet, but not body weight, control hypothalamic microglial activity

Oct 30, 2013Glia

Hormones and diet, but not body weight, influence immune cell activity in the brain’s control center

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Abstract

A significant increase in the total number of arcuate nucleus microglia was observed in mice after exposure to a high-fat diet.

Microglial activation in the hypothalamus may be linked to metabolic changes associated with obesity.
Ob/ob mice exhibited lower microglial activity compared to wild-type mice, which was reversed with leptin replacement.
Db/db mice had microglial activity similar to wild-type mice but demonstrated different patterns of microglial markers.
After two weeks on a high-fat diet, both ob/ob and db/db mice showed increases in specific microglial markers.
Gut signals and adipokines, rather than body weight alone, may influence hypothalamic microglial activity in obesity.

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The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity.

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Hormones and diet, but not body weight, control hypothalamic microglial activity

Abstract

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