Effects of Fasting and Feeding on Transcriptional and Posttranscriptional Regulation of Insulin-Degrading Enzyme in Mice

Cells

Malcolm A. Leissring¹  Sergio Diez-Hermano²  Carlos M. González-Casimiro³  Beatriz Merino³  Germán Perdomo³  Irene Cózar-Castellano³  Patricia Cámara-Torres³  Tamara Postigo-Casado³ 

[1] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND), Irvine, CA 92697-4545, USA;Institute for Research in Sustainable Forest Management (iuFOR), University of Valladolid, 34004 Palencia, Spain;Unidad de Excelencia Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, 47003 Valladolid, Spain;

关键词: insulin-degrading enzyme;    fasting;    refeeding;    insulin resistance;    liver;    metabolic adaptations;   

DOI  :  10.3390/cells10092446

来源: DOAJ

【 摘 要 】

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn²⁺-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD. Likewise, IDE protein levels were reduced in the skeletal muscle (~30%) of mice fed an HFD during the fasting state. Circulating lactate concentrations directly correlated with hepatic IDE activity and protein levels. Of note, L-lactate in liver lysates augmented IDE activity in a dose-dependent manner. Additionally, IDE protein levels in liver and muscle tissues, but not its activity, inversely correlated (R² = 0.3734 and 0.2951, respectively; p < 0.01) with a surrogate marker of insulin resistance (HOMA index). Finally, a multivariate analysis suggests that circulating insulin, glucose, non-esterified fatty acids, and lactate levels might be important in regulating IDE in liver and muscle tissues. Our results highlight that the nutritional regulation of IDE in liver and skeletal muscle is more complex than previously expected in mice, and that fasting/refeeding does not strongly influence the regulation of renal IDE.

【 授权许可】

Unknown