Mitochondrial regulation of energy efficiency

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DESCRIPTION (provided by applicant): Brown adipose tissue (BAT) is unique in its ability to acutely turn on uncoupling, leading to nutrient consumption and thermogenesis. As such, expansion of BAT is considered a potential strategy to reduce obesity in humans. New approaches to increase BAT mass have been developed, however the ability of fully differentiated BAT to dissipate energy by thermogenesis still remains dependent on adrenergic stimulation. Therefore, to obtain therapeutic benefit, expansion of BAT must be complemented by new approaches to activate BAT uncoupling and energy dissipation. Our studies indicate that in addition to lipolysis, adrenergic stimulation induces acute and robust changes to mitochondrial network architecture. These changes to mitochondria increase the ability of free fatty acids (FFA) to induce uncoupling and energy dissipation. We hypothesize that changes to mitochondrial dynamics serve as an amplification pathway for norepinephrine-induced uncoupling by enhancing the ability of FFA to activate UCP1 and by recruiting PTP as a secondary uncoupling mechanism. To address this hypothesis we will (i) study NE-unique changes to mitochondrial dynamics in the mouse brown adipocytes (BA) and human brite (brown in white) adipocytes, and determine the molecular mediators of these effects, (ii) quantify the extent to which mitochondrial dynamics acts as an amplification and sensitization pathway for energy dissipation in human brite and mouse BA in vitro and in vivo, and (iii) determine the mechanism by which changes to mitochondrial dynamics amplifies energy expenditure and increases sensitivity of BAT to FFA. This study will demonstrate that mitochondrial dynamics is a potential therapeutic point of intervention through which activation of BA uncoupling can be achieved at plasma levels of fatty acids, in the absence of adrenergic stimulation. Two pharmacological approaches to target mitochondrial dynamics will also be tested as a proof of concept for this approach, verifying the impact of changes to mitochondrial dynamics on BA uncoupling and energy dissipation.