Dietary L-arginine supplementation reduces fat mass in diet-induced obese rats

This study was conducted to test the hypothesis that dietary arginine supplementation reduces fat mass in diet-induced obese rats. Male Sprague-Dawley rats were fed either low- or high-fat diets for 15 wks (16 rats/diet). Thereafter, lean or obese rats continued to be fed their same respective diets and received drinking water containing either 1.51% L-arginine-HCl or 2.55% alanine (isonitrogenous control) (n=8/treatment group). Twelve weeks after the initiation of the arginine treatment, rats were euthanized to obtain tissues for biochemical analyses. Results were statistically analyzed as a 2x2 factorial experimental design using ANOVA. High-fat diet increased the mass of white adipose tissues at different anatomical locations by 49-96% compared to the low-fat diet. Concentrations of serum cholesterol as well as lipids in skeletal muscle and liver were higher in obese rats than in lean rats. L-Arginine supplementation reduced white adipose tissue mass by 20-40% while increasing brown adipose tissue mass by 15-20%. In addition, arginine treatment decreased adipocyte size, serum concentrations of glucose, triglycerides and leptin, improved glucose tolerance, and enhanced glucose and oleic acid oxidation in skeletal muscles. The mRNA levels for hepatic fatty acid synthase and stearoyl-CoA desaturase were reduced, but mRNA levels for hepatic AMP-activated protein kinase (AMPK), PPAR coactivator-1 and carnitine palmitoyltransferase I (CPT-I) as well as muscle CPT-I were increased in response to the arginine treatment. Subsequent experiments were conducted with cell models to define the direct effects of arginine on energy-substrate metabolism in insulin-sensitive cells. In BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes and 3T3-L1 mouse adipocytes, increasing extracellular concentrations of arginine from 0 to 400 ?M increased AMPK expression as well as glucose and oleic acid oxidation. Inhibition of nitric oxide synthesis moderately attenuated the arginine-stimulated increases of substrate oxidation as well as AMPK and ACC phosphorylation in BNL CL.2 cells, but had no effect in C2C12 and 3T3-L1 cells. Collectively, these results suggest that arginine increases AMPK expression and energy-substrate oxidation in a cell-specific manner, thereby reducing fat mass in diet-induced obese rats. The findings have important implications for treating obesity in humans and companion animals as well as decreasing fat deposition in livestock species.