title: Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity.
abstract: Thiazolidinediones (TZDs) are potent insulin-sensitizing compounds and high-affinity ligands for the transcription factor peroxisomal proliferator-activated receptor gamma. The mechanism through which TZDs improve insulin sensitivity, however, is not clear. In this study, we asked whether the ability of TZD to suppress and antagonize TNF alpha is an underlying mechanism for its molecular and physiological effects, using obese (ob/ob) mice lacking TNF alpha function. We found that the lipid-lowering effects of TZD are completely independent of TNF alpha suppression, and the insulin-sensitizing effects of TZD are partially independent. TZD treatment improved insulin sensitivity in ob/ob mice both with and without functional TNF alpha, albeit with different absolute potency. To characterize the potential interdependency of TZD- and TNF alpha-regulated pathways at the molecular level, we also performed four-way transcriptional profiling of white adipose tissue of TZD- and vehicle-treated ob/ob mice, with and without TNF alpha function. The majority of metabolic genes identified were regulated independent of the presence of TNF alpha, whereas most effects on inflammatory mediators were dependent on TNF alpha. This study demonstrates that the insulin-sensitizing action of TZD occurs partially through TNF-independent mechanisms, although a subset of the molecular effects of TZD treatment in adipose tissue depends on TNF alpha.
authors.affiliation: Division of Biological Sciences and Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
authors.forename: K Teoman
authors.initials: KT
authors.lastname: Uysal
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiesbrock
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D007700:Kinetics; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C089946:2,4-thiazolidinedione