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Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

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

Address correspondence and reprint requests to Yiying Zhang, PhD, Division of Molecular Genetics, Department of Pediatrics, Columbia University, Russ Berrie Pavilion, Rm. 620, 1150 St. Nicholas Ave., New York, NY 10032. E-mail: yz84{at}columbia.edu. Or Yi-Hao Yu, MD, PhD, Division of Preventive Medicine, Department of Medicine, Columbia University, 630 W. 168th St., PH 10-305J, New York, NY 10032. E-mail: yy102{at}columbia.edu

Abbreviations: BAT, brown adipose tissue; G6P, glucose-6-phosphatase; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of insulin resistance; mTOR, mammalian target of rapamycin; UCP, uncoupling protein; WAT, white adipose tissue

Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), 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 rodent 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 downregulation 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 libitum consumption of HFD likely via multiple mechanisms.

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