Diet-induced obesity is linked to increasingly prevalent metabolic diseases, including diabetes type 2, and current medications and dietary recommendations have not stemmed this tide. New, effective ways are therefore needed to reduce the metabolic impact of dietary excess. In response, a new wave of research is focusing on circuits in the hypothalamus, a brain area controlling food intake, body weight, and intermediary metabolism. These circuits go awry in response to dietary excess, prompting the intriguing idea of targeting hypothalamic dysfunction to lessen peripheral metabolic dysfunction. The long-term goal of this proposal is to control diet-induced hypothalamic dysfunction in order to limit metabolic disease. This goal has led to a focus on diet-induced inflammation, which in peripheral tissues involves macrophages and has been targeted to prevent insulin resistance and steatohepatitis. Interestingly, similar metabolic inflammation also occurs in the hypothalamus, and involves the accumulation of microglia, CNS analogs of macrophages. Strong preliminary data in mice reveal that microglia determine the severity of diet-induced hypothalamic inflammation, pointing to the value of targeting microglia for metabolic benefit. Long-chain saturated fatty acids (SFAs), which stimulate the inflammatory (M1) activation of macrophages, also stimulate the M1 activation hypothalamic microglia. Increasing the capacity of macrophages to store dietary SFAs in triacylglycerol (TG) reduces peripheral metabolic inflammation and insulin resistance in mice, however nearly nothing is known about microglial fat metabolism, providing a great opportunity for discovery. The central hypothesis of this proposal is that dietary SFAs traverse a fenestrated blood-brain barrier to enter the mediobasal hypothalamus, are taken up by microglia, and overwhelm glycerolipid pathways. This leads to hypothalamic microglial M1 activation and accumulation, producing a defined set of metabolic abnormalities. The objective of this proposal is to mitigate SFA-induced hypothalamic microglial activation and consequent metabolic dysfunction. It contains three aims, using innovative mouse models, to test the central hypothesis and reach this objective. The first focuses on circulating lipoproteins in delivering SFAs to hypothalamic microglia, and targets microglial lipoprotein lipase in order to protect microglia from SFA-induced activation. The second determines the impact of limiting microglial TG synthesis capacity on SFA-induced hypothalamic inflammation. The third uses new tools to limit or spontaneously induce M1 activation in hypothalamic microglia in order to determine the impact of hypothalamic microglial activation on glucose, fat, and energy metabolism. The impact of this proposal will be to open up a new frontier in metabolic research: that of manipulating microglial nutrient metabolism to control hypothalamic inflammation. This focus holds promise to define microglia as targets to mitigate the detrimental metabolic effects of dietary SFAs. By validating new strategies to control microglial function, the proposed work may benefit other areas from aging to cognitive sciences.

Public Health Relevance

Recent work has led to an emerging interest in targeting chronic diet-induced tissue inflammation, termed 'metabolic inflammation', as a means to mitigate the development of diseases linked to diet-induced obesity, including diabetes type 2. A new focus on inflammation in the hypothalamus, an area of the brain controlling important metabolic functions, lies at the forefront of metabolic inflammation research, and an array of preliminary observations reveal that inflammatory cell types called microglia respond to elevated levels of unhealthy dietary fats with inflammatory activation. This proposal uses innovative new techniques to explore how fats are sensed by hypothalamic microglia, and how these microglia modulate inflammatory processes to control metabolic health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103175-05
Application #
9648135
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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