Metabolic Fluxes in the Renal Cortex Are Dysregulated In Vivo in Response to High-Fat Diet

Diabetes and obesity are risk factors for kidney disease. Whereas renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here, we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57BL/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through ¹³C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared with chow-fed mice. Relative to the citric acid cycle, HF feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) and decreased flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from nonpyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.

• Diabetes and obesity are risk factors for kidney disease, yet the impact of diet-induced insulin resistance on renal metabolism is incompletely characterized.

• In vivo metabolic flux analysis of the renal cortex was performed in mice fed chow or high-fat diet that underwent a hyperinsulinemic-euglycemic clamp.

• In diet-induced insulin resistance, increased acetyl-CoA flux was derived from nonpyruvate substrates; this switch coincided with increased anaplerosis and accumulation of peroxidized lipid products in the renal cortex.

• The dysregulation in renal metabolic fluxes observed in diet-induced insulin resistance may instigate oxidative stress that sensitizes the kidney to injury.