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Grant Abstract: Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

Grant Number: 5R01DK097441-08
PI Name: Kajimura
Project Title: Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

Abstract: This application is an administrative supplement in response to the PA-18-817: Administrative Supplements for Research on Dietary Supplements. This supplement aims to expand the scope of the parent R01DK097441-08, entitled “Molecular Control of Brown Adipose Cell Fate and Energy Metabolism” which focuses on the role of a newly identified non-canonical adipose tissue thermogenesis (UCP1-independent Ca2+ cycling thermogenesis) in the regulation of energy expenditure and glucose metabolism. During studies examining the mechanisms of Ca2+ cycling thermogenesis in adipose tissue, we found that 1) adipose tissue thermogenesis is dramatically declined with age, 2) the age-associated attenuation in thermogenesis is tightly coupled with reduced activity of pyruvate dehydrogenase (PDH), the central regulator of glucose oxidation and Ca2+ cycling fat thermogenesis, and 3) the age-associated impairment in PDH activity is due to reduced mitochondrial lipoylation of the PDH complex (note: lipoylation in the PDH complex positively regulates its enzymatic activity). Unexpectedly, our preliminary studies found that oral supplementation of a-lipoic acids (R-(+) a-lipoic acid) – a natural short-chain fatty acid containing sulfhydryl groups that serve as a conjugate base for mitochondrial protein lipoylation – potently restores glucose oxidation in aged thermogenic fat by enhancing protein lipoylation of the PDH complex. Importantly, a-lipoic acid supplementation effectively prevents the age-associated bodyweight gain and glucose intolerance. These observations motivated us to further explore the mechanisms and therapeutic potential of oral a-lipoic acid supplementation for ameliorating age-associated obesity and glucose intolerance.

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