This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klover, P. J. Articles by Mooney, R. A. Search for Related Content PubMed PubMed Citation Articles by Klover, P. J. Articles by Mooney, R. A.

Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity

Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Address all correspondence and requests for reprints to: Dr. Robert A. Mooney, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642. E-mail: robert_mooney{at}urmc.rochester.edu.

Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lep^ob mice by injection of IL-6-neutralizing antibody. In untreated Lep^ob mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lep^ob mice, in contrast to only 32% in Lep^ob controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lep^ob mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer⁴⁷³) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

This article has been cited by other articles:

				L. S. Quinn, B. G. Anderson, L. Strait-Bodey, A. M. Stroud, and J. M. Argiles Oversecretion of interleukin-15 from skeletal muscle reduces adiposity Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E191 - E202. [Abstract] [Full Text] [PDF]

				Y. Tamura, M. Sugimoto, T. Murayama, Y. Ueda, H. Kanamori, K. Ono, H. Ariyasu, T. Akamizu, T. Kita, M. Yokode, et al. Inhibition of CCR2 Ameliorates Insulin Resistance and Hepatic Steatosis in db/db Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2195 - 2201. [Abstract] [Full Text] [PDF]

				J.-H. Kim, J. E. Kim, H.-Y. Liu, W. Cao, and J. Chen Regulation of Interleukin-6-induced Hepatic Insulin Resistance by Mammalian Target of Rapamycin through the STAT3-SOCS3 Pathway J. Biol. Chem., January 11, 2008; 283(2): 708 - 715. [Abstract] [Full Text] [PDF]

				K. J. Strissel, Z. Stancheva, H. Miyoshi, J. W. Perfield II, J. DeFuria, Z. Jick, A. S. Greenberg, and M. S. Obin Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications Diabetes, December 1, 2007; 56(12): 2910 - 2918. [Abstract] [Full Text] [PDF]

				D. Wu, Z. Ren, M. Pae, W. Guo, X. Cui, A. H. Merrill, and S. N. Meydani Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue J. Immunol., October 1, 2007; 179(7): 4829 - 4839. [Abstract] [Full Text] [PDF]

				J. C. O'Connor, C. L. Sherry, C. B. Guest, and G. G. Freund Type 2 Diabetes Impairs Insulin Receptor Substrate-2-Mediated Phosphatidylinositol 3-Kinase Activity in Primary Macrophages to Induce a State of Cytokine Resistance to IL-4 in Association with Overexpression of Suppressor of Cytokine Signaling-3 J. Immunol., June 1, 2007; 178(11): 6886 - 6893. [Abstract] [Full Text] [PDF]

				S. Glund, A. Deshmukh, Y. C. Long, T. Moller, H. A. Koistinen, K. Caidahl, J. R. Zierath, and A. Krook Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle Diabetes, June 1, 2007; 56(6): 1630 - 1637. [Abstract] [Full Text] [PDF]

				S. Musaad and E. N. Haynes Biomarkers of Obesity and Subsequent Cardiovascular Events Epidemiol. Rev., May 10, 2007; (2007) mxm005v1. [Abstract] [Full Text] [PDF]

				R. A. Mooney COUNTERPOINT: INTERLEUKIN-6 DOES NOT HAVE A BENEFICIAL ROLE IN INSULIN SENSITIVITY AND GLUCOSE HOMEOSTASIS J Appl Physiol, February 1, 2007; 102(2): 816 - 818. [Full Text] [PDF]

				REBUTTAL FROM DRS. PEDERSEN AND FEBBRAIO J Appl Physiol, February 1, 2007; 102(2): 818 - 818. [Full Text] [PDF]

				E. E. Spangenburg, S. E. Shoelson, C. Weigert, R. Lehmann, E. D. Schleicher, J.-O. Jansson, V. Wallenius, J.-P. Bastard, C. Lagathu, M. Caron, et al. Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis J Appl Physiol, February 1, 2007; 102(2): 820 - 823. [Full Text] [PDF]

				REBUTTAL FROM DR. MOONEY J Appl Physiol, February 1, 2007; 102(2): 818 - 819. [Full Text] [PDF]

				B. K. Pedersen, M. A. Febbraio, and R. A. Mooney Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis J Appl Physiol, February 1, 2007; 102(2): 814 - 816. [Full Text] [PDF]

				L. Al-Khalili, K. Bouzakri, S. Glund, F. Lonnqvist, H. A. Koistinen, and A. Krook Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle Mol. Endocrinol., December 1, 2006; 20(12): 3364 - 3375. [Abstract] [Full Text] [PDF]

				A. L. Carey, G. R. Steinberg, S. L. Macaulay, W. G. Thomas, A. G. Holmes, G. Ramm, O. Prelovsek, C. Hohnen-Behrens, M. J. Watt, D. E. James, et al. Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase. Diabetes, October 1, 2006; 55(10): 2688 - 2697. [Abstract] [Full Text] [PDF]

				M. A. M. den Boer, P. J. Voshol, J. P. Schroder-van der Elst, E. Korsheninnikova, D. M. Ouwens, F. Kuipers, L. M. Havekes, and J. A. Romijn Endogenous Interleukin-10 Protects against Hepatic Steatosis but Does Not Improve Insulin Sensitivity during High-Fat Feeding in Mice Endocrinology, October 1, 2006; 147(10): 4553 - 4558. [Abstract] [Full Text] [PDF]

				V. Vachharajani and S. Vital Obesity and sepsis. J Intensive Care Med, September 1, 2006; 21(5): 287 - 295. [Abstract] [PDF]

				I. Wernstedt, B. Olsson, M. Jernas, S. Paglialunga, L. M. S. Carlsson, U. Smith, K. Cianflone, K. Wallenius, and V. Wallenius Increased Levels of Acylation-Stimulating Protein in Interleukin-6-Deficient (IL-6-/-) Mice Endocrinology, June 1, 2006; 147(6): 2690 - 2695. [Abstract] [Full Text] [PDF]