Glucose, Cholesterol and Obesity Improved By Dietary Leucine Intake -
    • Glucose, Cholesterol and Obesity Improved By Dietary Leucine Intake

      Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms
      Yiying Zhang 1,2, Kaiying Guo 1, Robert E. LeBlanc 1, Daniella Loh 1, Gary J. Schwartz 3 and Yi-Hao Yu 4

      Author Affiliations

      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: 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:

      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.

      BAT, brown adipose tissueG6P, glucose-6-phosphataseHFD, high-fat dietHOMA-IR, homeostasis model assessment of insulin resistancemTOR, mammalian target of rapamycinUCP, uncoupling proteinWAT, white adipose tissue
      Despite the increased awareness of health risks associated with obesity and its attendant metabolic disorders, the prevalence of obesity has doubled in the past 20 years (1). Many dieting strategies have been developed and practiced in the past two decades, with variable short-term success rates (2,3). Long-term success in maintaining weight loss has proven to be difficult, in part because energy metabolism becomes more efficient at the reduced weight as a result of the normal physiological responses to weight loss and energy deficits (4,5).

      Manipulation of dietary composition of macronutrients merits careful investigation because macronutrients not only provide calories but some components may also function as signaling molecules to affect feeding behavior, energy balance, and fuel efficiency. Dietary supplementation is particularly attractive in that it may improve diet qualities and reduce cardiovascular risks associated with obesity and the metabolic syndrome without affecting the gross macronutrient compositions and the palatability of regular food, which will likely result in better long-term compliance.

      Leucine is an essential branched chain amino acid that cannot be produced and can only be obtained from diet in human. Leucine serves not only as a building block for protein synthesis but is also a potent activator of the mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in many cellular processes, including protein synthesis, cell growth, and metabolism (6–10). Indeed, leucine supplementation increases the net protein anabolism in various tissues (11–16). However, by activating mTOR and S6 kinase, leucine also feedback inhibits insulin signaling and decrease glucose utilization in skeletal muscle (17–20).

      Several recent studies have shown that protein-rich diets produce a better glycemic control and a greater loss of body fat and less of lean tissue during weight loss than do carbohydrate-rich diets with the same fat and caloric content (21–24). Branched chain amino acids, especially leucine, have been speculated to play a key role in this process (25). Supporting this hypothesis, Donato et al. (26) reported that leucine supplementation during caloric restriction also results in more fat loss and improves protein synthesis in liver and muscle. Recently, Seeley and colleagues (10) showed that infusion of leucine into the third ventricle of the rat brain decreases the animal's food intake and body weight via activation of the mTOR pathway in the arcuate nucleus of the hypothalamus. Thus, as leucine may function to promote fat loss while also, independently, increase insulin resistance in peripheral tissues (see above), it remains unclear whether increased leucine intake in animals affects the development of dietary obesity as well as whether it has an overall detrimental or beneficial health effect.

      We sought to determine the net effects of dietary supplementation of leucine on whole-body macronutrient and energy metabolism in mice with free access to a high-fat diet (HFD) and to assess how cardiovascular risks associated with diet-induced obesity may be modified by increased dietary leucine intake. Here, we show that doubling dietary leucine intake significantly reduces HFD-induced weight gain and improves hyperglycemia and hypercholesterolemia, which is associated with a previously unrecognized effect of leucine, i.e., increased resting energy expenditure. Furthermore, modifications of the various cardiometabolic risk factors associated with increased leucine intake appear to involve multiple mechanisms that are not solely dependent on reduced adiposity.

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