Role of estrogens in hypothalamic inflammation and metabolic regulation.

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Project Summary Obesity is a grave public health threat since it greatly increases the risk of highly morbid chronic diseases including type 2 diabetes, hypertension, cardiovascular disease, and many cancers. Currently, over 60 percent of Americans are overweight or obese, and the lack of effective therapies available for weight reduction make it imperative to focus on unraveling the mechanisms underlying obesity and its associated metabolic disorders. This proposal focuses on brain mechanisms by which sex steroids protect from obesity and its associated metabolic diseases. Premenopausal women have a lower rate of metabolic disorders than men of the same age, but this trend reverses after menopause with increase of weight gain, accumulation of visceral adiposity and increase in associated comorbidities. While estrogen replacement therapy can reverse many of these menopausal changes, the increased cancer and stroke risks associated with this therapy preclude its use for primary prevention, creating a demand for understanding the mechanisms by which estrogen protects from obesity and its associated metabolic risks. Growing evidence suggests that obesity is associated with hypothalamic neuronal injury, inflammation, and reactive gliosis, characterized by activation of local microglia (the macrophage of the brain). Rodent studies have demonstrated that reducing hypothalamic inflammation and microglial activation limits weight gain and the metabolic complications of diet-induced obesity. Similarly, estrogen reduces food intake, increases energy expenditure, and can potently suppress brain inflammation. In addition, female mice are more resistant to diet-associated microglial activation and weight gain, suggesting a potential link between estrogen and microglial signaling. Indeed, our preliminary observations demonstrate that estrogen deficiency increases signs of diet-induced hypothalamic inflammation and gliosis. These findings support studies proposed in Specific Aim 1 to use animal models with ablation of microglial inflammation to determine whether hypothalamic gliosis is required for Western-type diet and estrogen deficiency to synergistically predispose to obesity and its associated metabolic complications. Additionally, we have developed mouse models with microglia-specific deletion of either estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) to determine the requirement of microglial estrogen signaling to protect from diet-induced obesity (Aim 2). The proposed studies will advance our understanding of how estrogen deficiency confers metabolic risk and test a novel model of estrogen- mediated metabolic regulation through action in microglia. More broadly, this proposal will provide new central mechanisms to explain the higher metabolic risk observed in women with low estrogen levels, and new microglial targets for preclinical therapeutic trials to reduce this risk.