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

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posted on 2024-03-19, 18:27 authored by Clinton M. Hasenour, Deveena R. Banerjee, Jamey D. Young

Diabetes and obesity are risk factors for kidney disease. While 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 to chow-fed mice. Relative to the citric acid cycle, HF-feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) while decreasing flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from non-pyruvate 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.

Funding

This research was generously supported by NIH grants K01 DK135924 (CMH), R01 DK106348 (JDY), U01 CA235508 (JDY), P30 CA068485 (JDY). DRB was supported by the Vanderbilt Integrated Training in Engineering and Diabetes program (NIH grant T32 DK101003). Vanderbilt Mouse Metabolic Phenotyping Center and Hormone Assay and Analytical Services Core were supported by NIH grants U2C DK135073, P30 DK020593 and U24DK059637, S10OD025199.

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