Sex- and Dose-Dependent Effect of L-Citrulline on Body Weight and Food Intake in Obese Type 2 Diabetic Rats.

Background: Obesity and type 2 diabetes (T2D) are associated with nitric oxide (NO) deficiency. L-citrulline (Cit), a substrate for NO synthesis, has been suggested as a treatment for obesity and T2D. Objectives: This study aims to determine the effects of Cit on body weight, food intake, and water consumption in obese T2D male and female rats. Methods: The T2D was induced using a high-fat diet (HFD) and a low dose of streptozotocin (STZ). Obese male (n = 30) and female (n = 30) rats with T2D were divided into five groups (n = 6/group) that received Cit (0, 1, 4, 7, and 10 g/L in drinking water for 8 weeks). Body weight, food intake, and water consumption were measured every week. Serum Cit and nitrite+nitrate (NOx) concentrations were measured at weeks 0, 4, and 8, and serum fasting glucose was measured at week 8. Results: Compared to non-treated T2D rats, Cit-treated male rats had lower body weight (11.3%, 13.0%, and 11.6% at doses of 4, 7, and 10 g/L), lower food intake (4.7% and 5.5% at doses of 4 and 7 g/L), and water consumption (7% at dose 7 g/L). In female rats, Cit decreased body weight (7.2%, 8%, and 7.3% at doses of 4, 7, and 10 g/L), food intake (4.0% and 5.0% at doses of 4 and 7 g/L), and water consumption (5% and 6.6% at doses of 4 and 7 g/L; all P < 0.001). The body weight and food intake-lowering effects of Cit were higher in T2D male rats than females (all P < 0.05), but decreased water consumption was comparable between sexes. A Cit dose of 7 g/L was most effective in reducing all measured parameters in both sexes. Conclusions: The Cit decreased body weight, food intake, and water consumption in obese T2D male and female rats. These effects were sex- and dose-dependent.