Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

Sebastian Beck Jørgensen; 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

doi:10.2337/db12-0443

Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

Sebastian Beck Jørgensen, 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

PhD

95 Citations (Scopus)

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 language	English
Journal	Diabetes
Volume	62
Issue number	1
Pages (from-to)	56-64
Number of pages	9
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db12-0443
Publication status	Published - Jan 2013

Keywords

Animals
Insulin Receptor Substrate Proteins
Insulin Resistance
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal
Obesity
Phosphorylation
Suppressor of Cytokine Signaling Proteins
Triglycerides

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db12-0443

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Beck Jørgensen, S., O'Neill, H. M., Sylow, L., Honeyman, J., Hewitt, K. A., Palanivel, R., Fullerton, M. D., Öberg, L., Balendran, A., Galic, S., van der Poel, C., Trounce, I. A., Lynch, G. S., Schertzer, J. D., & 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

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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.",

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

AU - Beck Jørgensen, Sebastian

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

N1 - CURIS 2013 NEXS 284

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.

KW - Animals

KW - Insulin Receptor Substrate Proteins

KW - Insulin Resistance

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Muscle, Skeletal

KW - Obesity

KW - Phosphorylation

KW - Suppressor of Cytokine Signaling Proteins

KW - Triglycerides

U2 - 10.2337/db12-0443

DO - 10.2337/db12-0443

M3 - Journal article

C2 - 22961088

SN - 0012-1797

VL - 62

SP - 56

EP - 64

JO - Diabetes

JF - Diabetes

IS - 1

ER -

Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

Abstract

Keywords

UN SDGs

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