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

Qian Su, Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Juan Huang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Xi Chen, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Yijie Wang, Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Muqing Shao, Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Hongjia Yan, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, 400042, China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, 400042, China.
Fuwei Zhang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Yinxing Ni, Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology and Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20052, USA.
Jian Zhong, Department of Endocrinology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
Jian Yang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.

Document Type

Journal Article

Publication Date

2-1-2023

Journal

Molecular nutrition & food research

DOI

10.1002/mnfr.202200589

Keywords

high-fat diet; insulin clearance; insulin resistance; insulin-degrading enzyme; kidney

Abstract

SCOPE: 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. METHODS AND RESULTS: 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. CONCLUSION: Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.

Department

Medicine

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