We are proposing a novel metabolic mechanism that could explain how a high fat diet and/or abnormalities in fatty acid metabolism lead to obesity. As a first step, we will examine the premise that a key regulator of muscle fuel metabolism is malonyl CoA. Recent studies have led us to hypothesize that malonyl CoA and the enzyme that catalyzes its formation, acetyl-CoA carboxylase (ACC), are components of a fuel sensing and signalling mechanism that responds to changes in the fuel supply and energy expenditure of the muscle cell. The proposed studies will define further the conditions under which this mechanism operates, examine how it is regulated and test the notion that it modulates the metabolism of ketone bodies as well as that of fatty acids. They will also evaluate whether dysregulation of this mechanism, leading to a sustained increase in the concentration of malonyl CoA (in muscle and liver), could play a role in the pathogenesis of certain forms of obesity. Incubated rat muscles and intact rats will serve as experimental models.
The specific aims are as follows. 1. To confirm and extend observations indicating that a malonyl CoA fuel sensing and signalling mechanism operates in skeletal muscle. 2. To determine how the key enzyme in this fuel-sensing mechanism, acetyl CoA carboxylase (ACC), is regulated in the muscle cell. The roles of phosphorylation state, substrate supply, citrate and changes in enzyme protein will be evaluated. 3. To examine whether changes in the concentration of malonyl CoA regulate the beta-oxidation and secondarily the esterification of fatty acids in muscle. 4. To examine whether changes in the concentration of malonyl CoA regulate the metabolism of ketone bodies. 5. To assess why the concentration of malonyl CoA is chronically increased in muscle and liver of the Dahl salt-sensitive (Dahl-S) rat and whether it is associated with an impairment of fat oxidation (RQ measurement) and a predisposition to obesity. These studies should provide novel insights into the role of the malonyl CoA fuel-sensing and signalling mechanism in the regulation of fuel metabolism in muscle and other tissues. They should also provide evidence as to whether dysregulation of this mechanism resulting in high tissue concentrations of malonyl CoA is a risk factor for obesity.
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