TY - JOUR
T1 - The hyperglycemia-induced inflammatory response in adipocytes
T2 - The role of reactive oxygen species
AU - Lin, Ying
AU - Berg, Anders H.
AU - Iyengar, Puneeth
AU - Lam, Tony K.T.
AU - Giacca, Adria
AU - Combs, Terry P.
AU - Rajala, Michael W.
AU - Du, Xueliang
AU - Rollman, Brent
AU - Li, Weijie
AU - Hawkins, Meredith
AU - Barzilai, Nir
AU - Rhodes, Christopher J.
AU - Fantus, I. George
AU - Brownlee, Michael
AU - Scherer, Philipp E.
PY - 2005/2/11
Y1 - 2005/2/11
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M411863200
DO - 10.1074/jbc.M411863200
M3 - Article
C2 - 15536073
AN - SCOPUS:20044363264
SN - 0021-9258
VL - 280
SP - 4617
EP - 4626
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -