Long-Term High-Fat Diet Decreases Renal Insulin-Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway

ScopeLong-term high-fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin-degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD-induced obese mice. Methods and resultsTwenty four-weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK-2 cells. RNA-Seq analysis found that the PPAR pathway is involved. 24-weeks of HFD decreases renal PPAR gamma, but not PPAR alpha or PPAR beta/delta mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPAR gamma agonist rosiglitazone. The amount of PPAR gamma bound to the promoters of IDE is decreased in palmitic acid-treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice. ConclusionLong-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPAR gamma.

Automated summary

Long-term high-fat diet causes insulin resistance and impairs insulin clearance, with a decrease in renal IDE expression. The PPAR gamma pathway is involved in the inhibition of IDE expression by palmitic acid. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice.