The hyperglycemia-induced inflammatory response in adipocytes: The role of reactive oxygen species

Ying Lin, Anders H. Berg, Puneeth Iyengar, Tony K T Lam, Adria Giacca, Terry P. Combs, Michael W. Rajala, Xueliang Du, Brent Rollman, Weijie Li, Meredith Hawkins, Nir Barzilai, Christopher J. Rhodes, I. George Fantus, Michael Brownlee, Philipp E. Scherer

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367 Scopus citations

Abstract

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 hyperglycemia 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.

Original languageEnglish (US)
Pages (from-to)4617-4626
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number6
DOIs
StatePublished - Feb 11 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lin, Y., Berg, A. H., Iyengar, P., Lam, T. K. T., Giacca, A., Combs, T. P., Rajala, M. W., Du, X., Rollman, B., Li, W., Hawkins, M., Barzilai, N., Rhodes, C. J., Fantus, I. G., Brownlee, M., & Scherer, P. E. (2005). The hyperglycemia-induced inflammatory response in adipocytes: The role of reactive oxygen species. Journal of Biological Chemistry, 280(6), 4617-4626. https://doi.org/10.1074/jbc.M411863200