Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 11; pp. 2525 - 2535
• Main Authors: Hong, Eun-Gyoung, Ko, Hwi Jin, Cho, You-Ree, Kim, Hyo-Jeong, Ma, Zhexi, Yu, Tim Y., Friedline, Randall H., Kurt-Jones, Evelyn, Finberg, Robert, Fischer, Matthew A., Granger, Erica L., Norbury, Christopher C., Hauschka, Stephen D., Philbrick, William M., Lee, Chun-Geun, Elias, Jack A., Kim, Jason K.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2009
• Subjects: Animals; Biological and medical sciences; Creatine Kinase - genetics; Creatine Kinase - metabolism; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - physiology; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Dietary Fats - pharmacology; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Glucose; Glucose Clamp Technique; Homeostasis; Hyperinsulinism; Inflammation - physiopathology; Inflammation - prevention & control; Insulin - physiology; Insulin resistance; Insulin Resistance - physiology; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukin-10 - pharmacology; Macrophages - drug effects; Macrophages - physiology; Male; Medical sciences; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Muscle, Skeletal - physiopathology; Musculoskeletal system; Obesity; Original; Research design; Striated muscle. Tendons; Transgenic animals; Tumor necrosis factor-TNF; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Target tissue resistance; Diet; Diabetes mellitus; Interleukin; Cytokine; Metabolic diseases; Insulin resistance; Striated muscle; Feeding; Macrophage
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db08-1261

Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle Eun-Gyoung Hong 1 , 2 , Hwi Jin Ko 1 , 3 , You-Ree Cho 2 , Hyo-Jeong Kim 2 , Zhexi Ma 1 , Tim Y. Yu 2 , Randall H. Friedline 3 , Evelyn Kurt-Jones 4 , Robert Finberg 4 , Matthew A. Fischer 5 , Erica L. Granger 5 , Christopher C. Norbury 5 , Stephen D. Hauschka 6 , William M. Philbrick 2 , Chun-Geun Lee 7 , Jack A. Elias 7 and Jason K. Kim 1 , 2 , 3 , 4 1 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; 2 Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 3 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; 4 Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; 5 Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; 6 Department of Biochemistry, University of Washington, Seattle, Washington; 7 Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Corresponding author: Jason K. Kim, jason.kim{at}umassmed.edu . E.-G.H., H.J.K., and Y.-R.C. contributed equally and should be considered co–first authors. Abstract OBJECTIVE Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10). RESEARCH DESIGN AND METHODS MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses. RESULTS MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-α, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle. CONCLUSIONS These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes. Footnotes E.-G.H. is currently affiliated with Hallym University College of Medicine, Seoul, South Korea. Y.-R.C. is currently affiliated with the University of Texas Southwestern Medical Center, Dallas, Texas. H.-J.K. is currently affiliated with Eulji University College of Medicine, Seoul, South Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received September 11, 2008. Accepted August 2, 2009. © 2009 American Diabetes Association