MMPC :: MICROMouse Program Application Abstract

MICROMouse Program Application Abstract

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REMODELING OF HEPATIC LIPID METABOLISM BY DIETARY METHIONINE RESTRICTION

Thomas W Gettys (Baton Rouge, LA)

MICROMouse Program

Reduction of dietary methionine from normal levels of 0.86% to 0.17% (dietary MR) produces a substantial long term increase in food consumption, energy expenditure, and reduction in fat deposition in rodents. During the transition from fasting to the fed state, dietary MR produces a 40-50% greater increase in night time energy expenditure (EE) and an exaggerated increase in respiratory quotient (RQ) to greater than 1, indicative of a complete shift to carbohydrate oxidation in conjunction with increased de novo lipogenesis. The reciprocal shift to fat oxidation during fasting was also more complete in MR (RQ ~0.75) versus controls (RQ ~ 0.85). Hyperinsulinemic-euglycemic clamps show that dietary MR increases overall insulin sensitivity and tissue-specific uptake of glucose by an average of 2.5 fold. The transcriptional response to dietary MR among peripheral tissues includes a coordinated decrease in hepatic expression of genes associated with lipid synthesis and export from the liver, and a corresponding decrease in tissue and circulating lipids. In contrast, genes associated with de novo lipogenesis are upregulated in adipose tissue by dietary MR. These data are uniformly consistent with the hypothesis that dietary MR modifies the integration of lipid and carbohydrate metabolism in a way that creates inefficient, energy wasting substrate cycles between liver and adipose tissue. However, the benefits which acrue from this metabolic inefficiency include enhanced metabolic flexibility and insulin sensitivity in conjunction with reduced fat deposition and lipid profiles. The next logical series of experiments, outlined in this proposal, will be to establish the in vivo efficacy of dietary MR in a genetic model of obesity, insulin resistance, and aberrant lipid metabolism (KKaY mouse). We will use a combination of approaches to measure the physiological, biochemical, and metabolomic phenotype of the KKaY mouse and the specific effects of dietary MR on each component of that phenotype. The critical unanswered question addressed herein is how dietary MR remodels hepatic lipid metabolism to affect substrate cycling, increase EE, limit fat deposition, and increase insulin sensitivity.

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