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

Enxuan Jing, Pragalath Sundararajan, Ishita Deb Majumdar, Suwagmani Hazarika, Samantha Fowler, Angela Szeto, Stephane Gesta, Armando J Mendez, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number0767
JournalNutrition and Metabolism
Volume15
Issue number1
DOIs
StatePublished - Feb 2 2018

Fingerprint

Obese Mice
Insulin Resistance
Diet
Skeletal Muscle
Glucose
Skeletal Myoblasts
Protein Isoforms
Insulin
Messenger RNA
Long-Chain Acyl-CoA Dehydrogenase
Phosphofructokinase-1
Pyruvate Dehydrogenase Complex
Glycogen Synthase
Antisense Oligonucleotides
Metabolic Diseases
Negotiating
Oligonucleotides
Serine
Small Interfering RNA
Respiration

Keywords

  • Diabetes
  • Glucose metabolism
  • Heat shock protein 90
  • Hyperglycemia
  • Insulin resistance

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

Jing, E., Sundararajan, P., Majumdar, I. D., Hazarika, S., Fowler, S., Szeto, A., ... Narain, N. R. (2018). Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance. Nutrition and Metabolism, 15(1), [0767]. https://doi.org/10.1186/s12986-018-0242-6

Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance. / Jing, Enxuan; Sundararajan, Pragalath; Majumdar, Ishita Deb; Hazarika, Suwagmani; Fowler, Samantha; Szeto, Angela; Gesta, Stephane; Mendez, Armando J; Vishnudas, Vivek K.; Sarangarajan, Rangaprasad; Narain, Niven R.

In: Nutrition and Metabolism, Vol. 15, No. 1, 0767, 02.02.2018.

Research output: Contribution to journalArticle

Jing, E, Sundararajan, P, Majumdar, ID, Hazarika, S, Fowler, S, Szeto, A, Gesta, S, Mendez, AJ, Vishnudas, VK, Sarangarajan, R & Narain, NR 2018, 'Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance', Nutrition and Metabolism, vol. 15, no. 1, 0767. https://doi.org/10.1186/s12986-018-0242-6
Jing, Enxuan ; Sundararajan, Pragalath ; Majumdar, Ishita Deb ; Hazarika, Suwagmani ; Fowler, Samantha ; Szeto, Angela ; Gesta, Stephane ; Mendez, Armando J ; Vishnudas, Vivek K. ; Sarangarajan, Rangaprasad ; Narain, Niven R. / Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance. In: Nutrition and Metabolism. 2018 ; Vol. 15, No. 1.
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AU - Jing, Enxuan

AU - Sundararajan, Pragalath

AU - Majumdar, Ishita Deb

AU - Hazarika, Suwagmani

AU - Fowler, Samantha

AU - Szeto, Angela

AU - Gesta, Stephane

AU - Mendez, Armando J

AU - Vishnudas, Vivek K.

AU - Sarangarajan, Rangaprasad

AU - Narain, Niven R.

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N2 - 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.

AB - 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.

KW - Diabetes

KW - Glucose metabolism

KW - Heat shock protein 90

KW - Hyperglycemia

KW - Insulin resistance

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