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J. Biol. Chem., Vol. 280, Issue 6, 4617-4626, February 11, 2005
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The Hyperglycemia-induced Inflammatory Response in Adipocytes
THE ROLE OF REACTIVE OXYGEN SPECIES*
**¶¶
From the
Departments of Cell Biology, ¶Pathology, and **Medicine, and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, the Departments of Medicine and Physiology and Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario M5G 1X5, Canada, the ||ABR-Affinity BioReagents, Golden, Colorado 80403, and the Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122
Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mM to cells differentiated at 25 mM glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mM glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.
Received for publication, October 19, 2004
* This work was supported by Grant R01-HL-073163-01 (to Y. L.), an American Diabetes Association Medical Scientist Training grant (to A. H. B.), National Institutes of Health Medical Scientist Training Grant T32-GM07288 (to P. I. and M. W. R.), National Institutes of Health National Research Service Award DK61228 (to T. P. C.), Canadian Institutes of Health Research Grant MOP-38009 (to I. G. F.), National Institutes of Health Grants P01-AG021654 (to N. B. and M. B.), 1R01-DK55758 (to P. E. S.), and Juvenile Diabetes Research Foundation Award 1-2001-780 (to P. E. S.). 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.
¶¶ To whom correspondence should be addressed. Tel.: 718-430-2928; Fax: 718-430-8574; E-mail: scherer{at}aecom.yu.edu.
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