Regulating energy expenditure in adipose tissue

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Abstract There is little doubt that we are in the midst of a worldwide epidemic of obesity and diabetes. Recent data suggest an inflammatory link between obesity and insulin resistance. This proposal will focus on adaptive changes in energy expenditure during caloric overload and restriction, and explore a novel hypothesis that may directly lead to new therapeutic approaches. We hypothesize that that activation and induction of the protein kinase TBK1 in obesity and fasting reprograms metabolism to promote anabolic and repress catabolic pathways, tipping the scales towards energy storage and away from expenditure. These conclusions are derived from changes observed in mouse knockout mice, and in patients treated with the TBK1 inhibitor amlexanox. Specifically, activation or induction of TBK1 represses AMPK activity, inhibiting lipid oxidation and mitochondrial biogenesis while increasing lipogenesis. We will explore this hypothesis with three aims: 1) We will evaluate the temporal and spatial aspects of TBK1 activation and induction during obesity, and characterize the underlying mechanism; 2) We will explore the activation and induction of TBK1 during fasting, and elucidate the molecular mechanisms; 3) We will assess the role of the TBK1/AMPK axis in controlling metabolism during obesity and fasting via development of compound knockout mouse models, and evaluate the temporal and spatial aspects of this regulation. These findings may reveal how energy expenditure is repressed during caloric excess and restriction, and provide new therapeutic approaches to these devastating diseases.