title: The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.
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 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Anders H
authors.initials: AH
authors.lastname: Berg
authors.forename: Puneeth
authors.initials: P
authors.lastname: Iyengar
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: Terry P
authors.initials: TP
authors.lastname: Combs
authors.forename: Michael W
authors.initials: MW
authors.lastname: Rajala
authors.forename: Xueliang
authors.initials: X
authors.lastname: Du
authors.forename: Brent
authors.initials: B
authors.lastname: Rollman
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.forename: Meredith
authors.initials: M
authors.lastname: Hawkins
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: I George
authors.initials: IG
authors.lastname: Fantus
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D041721:3T3-L1 Cells; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000737:chemistry; D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D015151:Immunoblotting; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D029382:Dicarboxylic Acid Transporters; D007328:Insulin; D015850:Interleukin-6; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013311:Streptozocin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005947:Glucose; D010100:Oxygen; D000111:Acetylcysteine