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

• Published in: Experimental biology and medicine (Maywood, N.J.) N.J.), 2019-10, Vol.244 (13), p.1081-1088
• Main Authors: Tekwe, Carmen D, Yao, Kang, Lei, Jian, Li, Xilong, Gupta, Anand, Luan, Yuanyuan, Meininger, Cynthia J, Bazer, Fuller W, Wu, Guoyao
• Format: Article
• Language: English
• ISSN: 1535-3702; 1535-3699
• DOI: 10.1177/1535370219865229

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