Dietary Proteins Impact Glucose Tolerance and Hepatic Insulin Resistance in Mice through Modulation of the Urea Cycle

We recently reported that dietary proteins (DP) modulate diet-induced obesity and insulin resistance in mice (Nat Commun 12: 3377, 2021). We posit that these metabolic alterations are caused by differential activation of the hepatic urea cycle in response to different amino acid (AA) compositions and total nitrogen load. Objective: To test whether DP sources alter hepatic metabolism and insulin resistance through the urea cycle. Methods: Metabolic phenotypes, hepatic urea cycle and insulin resistance were measured in mice fed low-fat, low-sucrose (LFLS) or high-fat, high-sucrose (HFHS) diets containing either pork (PP), soy (SP) or casein (CP) protein for 12 weeks. Based on their AA composition, PP had the highest nitrogen load, followed by SP and CP. Results: When compared to SP and CP, feeding PP to HFHS mice induced more glucose intolerance which was correlated with higher post-prandial AA-derived nitrogen load in the portal vein. PP feeding in HFHS mice induced hepatic insulin resistance, revealed by impaired insulin-induced Akt phosphorylation on Ser473. Mice fed the LFLS diet were, however, protected from PP-induced glucose intolerance and insulin resistance, and this was associated with robust increase in the protein levels of urea cycle enzymes (CPS1, OTC) in the liver. In starked contrast, induction of urea cycle enzymes was blunted in the liver of PP-fed HFHS mice. PP feeding also increased the expression of inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) as showed by DHE staining of liver sections. Conclusion: Dietary PP increases total nitrogen load activating the urea cycle, which may protect against metabolic dysfunction and hepatic insulin resistance in LFLS mice. This protective mechanism is lost in PP-fed HFHS mice, likely by downregulation of urea cycle activity, when the liver is overloaded with dietary fat. iNOS induction could be acting as an alternative nitrogen handling pathway, causing a build-up of mitochondrial ROS. Disclosure F.Bégin: None. A.Caron: None. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti.