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

Abstract

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 HFDfed 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.

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

“…The role of BCAAs as substrates for protein synthesis is well documented. Recent studies have shown that BCAAs improve glucose and cholesterol metabolism in mice [14] and decrease insulin resistance in adipocytes by the insulin-signaling pathway [36]. Our present results demonstrate for the first time that leucine and isoleucine induce a concentration-dependent increase in GLP-1 release.…”

“…Total RNA (1 μg) was reverse-transcribed using Superscript II Reverse Transcriptase (Invitrogen, Carlsbad, CA, USA) with oligo-d(T) [12][13][14][15][16][17][18] as primer. After reverse transcription, the same batch of diluted cDNA was subjected to real-time polymerase chain reaction (PCR) to amplify target genes.…”

“…As regulators of protein metabolism, branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) have also been reported to improve glucose and cholesterol metabolism [13,14] and control appetite [15]. A study by Bowen et al [16] suggested that the protein component of dairy appears to be more important for weight loss than calcium in over-weight adults.…”

Leucine Facilitates Insulin Signaling through a Gαi Protein-dependent Signaling Pathway in Hepatocytes

“…Exposure of cultured skeletal muscle cells, adipocytes, or hepatocytes to amino acids or leucine can induce insulin resistance (10 -12). In contrast, some studies have shown that leucine supplementation does not have an effect on the development of insulin resistance or can even improve insulin sensitivity and prevent the diet-induced obesity (13,14). Explanations for these conflicting results are lacking and exact mechanism by which leucine modulates insulin sensitivity has not been established.…”

“…Theoretically, leucine is capable of modulating insulin signaling through the mammalian target of rapamycin (mTOR) 3 and S6K-mediated serine phosphorylations of IRS1/2 (3,21). It is noteworthy that supplementation of leucine can increase insulin sensitivity in obese animals (13,14), and the increased level of branched chain amino acids by knocking out the ratelimiting enzyme that catabolizes branched chain amino acids is associated with increased and not decreased insulin sensitivity (22). The increased insulin sensitivity by branched chain amino acids can be at least partially explained by decreased food intake and elevated energy expenditure (13,14,22).…”