Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance

Nutrition & Metabolism

Ishita Deb Majumdar¹  Armando J. Mendez¹  Niven R. Narain¹  Pragalath Sundararajan¹  Vivek K. Vishnudas¹  Stephane Gesta¹  Suwagmani Hazarika¹  Samantha Fowler¹  Rangaprasad Sarangarajan¹  Enxuan Jing¹  Angela Szeto² 

[1] BERG, LLC;Diabetes Research Institute, University of Miami Miller School of Medicine, University of Miami;

关键词: Heat shock protein 90;    Diabetes;    Hyperglycemia;    Insulin resistance;    Glucose metabolism;   

DOI  :  10.1186/s12986-018-0242-6

来源: DOAJ

【 摘 要 】

Abstract Background Inhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. In the present report, the specific isoform Hsp90ab1, was identified as playing a major role in regulating insulin signaling and glucose metabolism. Methods In a diet-induced obese (DIO) mouse model of diabetes, expression of various Hsp90 isoforms in skeletal tissue was examined. Subsequent experiments characterized the role of Hsp90ab1 isoform in glucose metabolism and insulin signaling in primary human skeletal muscle myoblasts (HSMM) and a DIO mouse model. Results In DIO mice Hsp90ab1 mRNA was upregulated in skeletal muscle compared to lean mice and knockdown using anti-sense oligonucleotide (ASO) resulted in reduced expression in skeletal muscle that was associated with improved glucose tolerance, reduced fed glucose and fed insulin levels compared to DIO mice that were treated with a negative control oligonucleotide. In addition, knockdown of HSP90ab1 in DIO mice was associated with reduced pyruvate dehydrogenase kinase-4 mRNA and phosphorylation of the muscle pyruvate dehydrogenase complex (at serine 232, 293 and 300), but increased phosphofructokinase 1, glycogen synthase 1 and long-chain specific acyl-CoA dehydrogenase mRNA. In HSMM, siRNA knockdown of Hsp90ab1 induced an increase in substrate metabolism, mitochondrial respiration capacity, and insulin sensitivity, providing further evidence for the role of Hsp90ab1 in metabolism. Conclusions The data support a novel role for Hsp90ab1 in arbitrating skeletal muscle plasticity via modulation of substrate utilization including glucose and fatty acids in normal and disease conditions. Hsp90ab1 represents a novel target for potential treatment of metabolic disease including diabetes.

【 授权许可】

Unknown