Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism

Jessica P.S. Marshall, Emma Estevez, Helene L. Kammoun, Emily J. King, Clinton R. Bruce, Brian G. Drew, Hongwei Qian, Peter Iliades, Paul Gregorevic, Mark A. Febbraio, Darren C. Henstridge

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. Materials and methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. Results: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. Conclusions: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.

Original languageEnglish
Pages (from-to)1928-1936
Number of pages9
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • body composition
  • energy regulation
  • glucose metabolism
  • insulin resistance
  • mouse model

Cite this

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title = "Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism",
abstract = "Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. Materials and methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. Results: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. Conclusions: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.",
keywords = "body composition, energy regulation, glucose metabolism, insulin resistance, mouse model",
author = "Marshall, {Jessica P.S.} and Emma Estevez and Kammoun, {Helene L.} and King, {Emily J.} and Bruce, {Clinton R.} and Drew, {Brian G.} and Hongwei Qian and Peter Iliades and Paul Gregorevic and Febbraio, {Mark A.} and Henstridge, {Darren C.}",
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language = "English",
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Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism. / Marshall, Jessica P.S.; Estevez, Emma; Kammoun, Helene L.; King, Emily J.; Bruce, Clinton R.; Drew, Brian G.; Qian, Hongwei; Iliades, Peter; Gregorevic, Paul; Febbraio, Mark A.; Henstridge, Darren C.

In: Diabetes, Obesity and Metabolism, Vol. 20, No. 8, 01.08.2018, p. 1928-1936.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism

AU - Marshall, Jessica P.S.

AU - Estevez, Emma

AU - Kammoun, Helene L.

AU - King, Emily J.

AU - Bruce, Clinton R.

AU - Drew, Brian G.

AU - Qian, Hongwei

AU - Iliades, Peter

AU - Gregorevic, Paul

AU - Febbraio, Mark A.

AU - Henstridge, Darren C.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. Materials and methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. Results: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. Conclusions: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.

AB - Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance. Materials and methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction. Results: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels. Conclusions: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.

KW - body composition

KW - energy regulation

KW - glucose metabolism

KW - insulin resistance

KW - mouse model

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U2 - 10.1111/dom.13319

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SN - 1463-1326

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