Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

Sebastian Beck Jorgensen, Hayley M O'Neill, Lykke Sylow, Jane Honeyman, Kimberly A Hewitt, Rengasamy Palanivel, Morgan D Fullerton, Lisa Öberg, Anudharan Balendran, Sandra Galic, Chris van der Poel, Ian A Trounce, Gordon S Lynch, Jonathan D Schertzer, Gregory R Steinberg

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Abstract

Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance.

Original languageEnglish
Pages (from-to)56-64
Number of pages9
JournalDiabetes
Volume62
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

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Insulin Resistance
Skeletal Muscle
Obesity
Energy Metabolism
Muscle Development
Cytokines
Insulin Receptor Substrate Proteins
Glucose Intolerance
Adiposity
Hyperinsulinism
High Fat Diet
Appetite
Leptin
Hypothalamus
Adipose Tissue
Signal Transduction
Phosphorylation
Insulin
Inflammation
Glucose

Cite this

Jorgensen, S. B., O'Neill, H. M., Sylow, L., Honeyman, J., Hewitt, K. A., Palanivel, R., ... Steinberg, G. R. (2013). Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes, 62(1), 56-64. https://doi.org/10.2337/db12-0443
Jorgensen, Sebastian Beck ; O'Neill, Hayley M ; Sylow, Lykke ; Honeyman, Jane ; Hewitt, Kimberly A ; Palanivel, Rengasamy ; Fullerton, Morgan D ; Öberg, Lisa ; Balendran, Anudharan ; Galic, Sandra ; van der Poel, Chris ; Trounce, Ian A ; Lynch, Gordon S ; Schertzer, Jonathan D ; Steinberg, Gregory R. / Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. In: Diabetes. 2013 ; Vol. 62, No. 1. pp. 56-64.
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abstract = "Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance.",
author = "Jorgensen, {Sebastian Beck} and O'Neill, {Hayley M} and Lykke Sylow and Jane Honeyman and Hewitt, {Kimberly A} and Rengasamy Palanivel and Fullerton, {Morgan D} and Lisa {\"O}berg and Anudharan Balendran and Sandra Galic and {van der Poel}, Chris and Trounce, {Ian A} and Lynch, {Gordon S} and Schertzer, {Jonathan D} and Steinberg, {Gregory R}",
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Jorgensen, SB, O'Neill, HM, Sylow, L, Honeyman, J, Hewitt, KA, Palanivel, R, Fullerton, MD, Öberg, L, Balendran, A, Galic, S, van der Poel, C, Trounce, IA, Lynch, GS, Schertzer, JD & Steinberg, GR 2013, 'Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity' Diabetes, vol. 62, no. 1, pp. 56-64. https://doi.org/10.2337/db12-0443

Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. / Jorgensen, Sebastian Beck; O'Neill, Hayley M; Sylow, Lykke; Honeyman, Jane; Hewitt, Kimberly A; Palanivel, Rengasamy; Fullerton, Morgan D; Öberg, Lisa; Balendran, Anudharan; Galic, Sandra; van der Poel, Chris; Trounce, Ian A; Lynch, Gordon S; Schertzer, Jonathan D; Steinberg, Gregory R.

In: Diabetes, Vol. 62, No. 1, 01.2013, p. 56-64.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

AU - Jorgensen, Sebastian Beck

AU - O'Neill, Hayley M

AU - Sylow, Lykke

AU - Honeyman, Jane

AU - Hewitt, Kimberly A

AU - Palanivel, Rengasamy

AU - Fullerton, Morgan D

AU - Öberg, Lisa

AU - Balendran, Anudharan

AU - Galic, Sandra

AU - van der Poel, Chris

AU - Trounce, Ian A

AU - Lynch, Gordon S

AU - Schertzer, Jonathan D

AU - Steinberg, Gregory R

PY - 2013/1

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N2 - Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance.

AB - Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance.

U2 - 10.2337/db12-0443

DO - 10.2337/db12-0443

M3 - Article

VL - 62

SP - 56

EP - 64

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 1

ER -

Jorgensen SB, O'Neill HM, Sylow L, Honeyman J, Hewitt KA, Palanivel R et al. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes. 2013 Jan;62(1):56-64. https://doi.org/10.2337/db12-0443