Oral administration of α-ketoglutarate enhances nitric oxide synthesis by endothelial cells and whole-body insulin sensitivity in diet-induced obese rats

Abstract

Obesity is a risk factor for many chronic diseases, including hypertension, type-2 diabetes, and cancer. Interestingly, concentrations of branched-chain amino acids (BCAAs) in plasma are commonly associated with endothelial dysfunction in humans and animals with obesity. Because L-leucine inhibits nitric oxide synthesis by endothelial cells (EC), we hypothesized that dietary supplementation with AKG (a substrate for BCAA transaminase) may stimulate BCAA catabolism in the small intestine and extra-intestinal tissues, thereby reducing the circulating concentrations of BCAAs and increasing nitric oxide synthesis by endothelial cells. Beginning at four weeks of age, male Sprague-Dawley rats were fed a low-fat or a high-fat diet for 15 weeks. At 19 weeks of age, lean or obese rats continued to be fed for 12 weeks their respective diets and received drinking water containing 0 or 1% AKG ( n =  8/group). At 31 weeks of age, the rats were euthanized to obtain tissues. Food intake did not differ ( P >  0.05) between rats supplemented with or without AKG. Oral administration of AKG (250 mg/kg BW per day) reduced ( P <  0.05) concentrations of BCAAs, glucose, ammonia, and triacylglycerols in plasma, adiposity, and glutamine:fructose-6-phosphate transaminase activity in endothelial cells, and enhanced ( P <  0.05) concentrations of the reduced form of glutathione in tissues, nitric oxide synthesis by endothelial cells, and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in both low-fat and high-fat rats. AKG administration reduced ( P <  0.05) white adipose tissue weights of rats in the low-fat and high-fat groups. These novel results indicate that AKG can reduce adiposity and increase nitric oxide production by endothelial cells in diet-induced obese rats. Impact statement Obesity is associated with elevated concentrations of branched-chain amino acids, including L-leucine. L-Leucine inhibits the synthesis of nitric oxide from L-arginine by endothelial cells, contributing to impairments in angiogenesis, blood flow, and vascular dysfunction, as well as insulin resistance. Reduction in the circulating levels of branched-chain amino acids through dietary supplementation with α-ketoglutarate to promote their transamination in the small intestine and other tissues can restore nitric oxide synthesis in the vasculature and reduce the weights of white adipose tissues, thereby improving metabolic profiles and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in diet-induced obese rats. Our findings provide a simple and effective nutritional means to alleviate metabolic syndrome in obese subjects. This is highly significant to combat the current obesity epidemic and associated health problems in humans worldwide.