Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance
| Autor: | Vivek K. Vishnudas, Samantha Fowler, Angela Szeto, Suwagmani Hazarika, Enxuan Jing, Stephane Gesta, Pragalath Sundararajan, Niven R. Narain, Rangaprasad Sarangarajan, Armando J. Mendez, Ishita Deb Majumdar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Medicine (miscellaneous) lcsh:TX341-641 Carbohydrate metabolism 03 medical and health sciences 0302 clinical medicine Insulin resistance Diabetes Glucose metabolism Hyperglycemia Heat shock protein 90 Internal medicine medicine Myocyte Glycogen synthase lcsh:RC620-627 Gene knockdown Nutrition and Dietetics biology Chemistry Insulin Research Skeletal muscle medicine.disease Insulin receptor lcsh:Nutritional diseases. Deficiency diseases 030104 developmental biology Endocrinology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein lcsh:Nutrition. Foods and food supply |
| Zdroj: | Nutrition & metabolism, 15:11 Nutrition & Metabolism, Vol 15, Iss 1, Pp 1-10 (2018) Nutrition & Metabolism |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s12986-018-0242-6) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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