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Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multi-mechanisms

¹Department of Pediatrics, Division of Molecular Genetics
²Naomi Berrie Diabetes Center
³Department of Medicine, Division of Preventive Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
⁴Department of Medicine & Neuroscience, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461

Correspondence: yz84{at}columbia.edu

Correspondence: yy102{at}columbia.edu

Leucine, as an essential amino acid and activator of mTOR, promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (p<0.05) and a 25% decrease in adiposity (p<0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and down-regulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL-cholesterol were decreased by 27% (p<0.001) and 53% (p<0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad lib consumption of HFD likely via multiple mechanisms.

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