Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Mol Nutr Food Res. 2023 Apr;67(7):e2200589. doi: 10.1002/mnfr.202200589. Epub 2023 Feb 21.
Long-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.
Twenty 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 PPARγ, but not PPARα or PPARβ/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ 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.
Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.
长期高脂肪饮食（HFD）会导致胰岛素抵抗，这是肥胖和 2 型糖尿病发展的主要病因。胰岛素清除受损不仅是胰岛素抵抗的后果，也是其原因。肾脏是胰岛素清除的主要部位，其中胰岛素降解酶（IDE）在近端小管中起着至关重要的作用。因此，本研究探讨了肾脏 IDE 在 HFD 诱导的肥胖小鼠胰岛素抵抗调节中的作用。
C57BL/6 小鼠 24 周的 HFD 导致胰岛素抵抗和胰岛素清除受损，同时伴有肾脏 IDE 表达和活性降低。棕榈酸可降低 HK-2 细胞中的 IDE mRNA 和蛋白表达。RNA-Seq 分析发现 PPAR 通路参与其中。24 周的 HFD 降低了肾脏的 PPARγ，但不降低 PPARα 或 PPARβ/δ mRNA 表达。棕榈酸对 IDE 表达的抑制作用可被 PPARγ 激动剂罗格列酮所预防。在棕榈酸处理的细胞中，与 IDE 启动子结合的 PPARγ 量减少。罗格列酮可改善 HFD 喂养小鼠的胰岛素清除和胰岛素抵抗，并增加肾脏 IDE 的表达。
长期 HFD 降低肾脏 IDE 的表达和活性，并导致胰岛素抵抗，这涉及到 PPARγ。
