While there is substantial evidence that the kidney is insulin responsive, it is unclear whether the organ becomes insulin resistant. Here, we investigate whether the kidney is susceptible to lipid-induced insulin resistance and, if so, whether insulin resistance may be mediated by increases in plasma membrane sn-1,2-diacylglycerol (DAG) content and activation of Protein Kinase Cε (PKCε). We studied 14 week old C57BL/6J mice fed either regular chow (RC) or a high fat diet (HFD) for three weeks. Infusion of [13C6]glucose under hyperinsulinemic-euglycemic clamp (HEC) conditions revealed HFD fed mice to have an ~40% reduction (P<0.01) in renal cortical mitochondrial pyruvate dehydrogenase flux relative to citrate synthase flux (VPDH/VCS) compared to RC mice. Next, we infused RC mice with a lipid emulsion (Intralipid® 20%) (RC+IL) during HEC. Despite matched plasma NEFAs at the clamp conclusion, renal cortical VPDH/VCS was significantly higher in RC+IL mice than in HFD mice (P<0.02). These findings suggest that reductions in insulin-stimulated mitochondrial VPDH/VCS observed in HFD mice are intrinsic to the kidney and cannot be attributed to alterations in fatty acid flux to the kidney. Consistent with our mitochondrial flux data, we found that feeding a HFD induced a defect in insulin signaling at the level of the insulin receptor (INSR) as evidenced by ~50% reductions in both insulin-stimulated INSRY1162 (P<0.05) and AKTS473 phosphorylation (P<0.001). HFD-induced reductions in insulin signaling were associated with an ~2-fold increase (P<0.01) in plasma membrane sn-1,2-DAG content, which was associated with an ~4-fold increase (P<0.05) in PKCε translocation.
Conclusion: HFD feeding induces insulin resistance in the renal cortex at the level of INSRY1162 phosphorylation. This defect in INSR signaling is associated with reduced insulin-stimulated pyruvate oxidation and may be mediated by a sn-1,2-DAG-PKCε-INSR mechanism.
B. T. Hubbard: None. R. C. Gaspar: None. D. Zhang: None. M. Kahn: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. X. Zhang: None. G. Cline: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company.