title: Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance.
abstract: Insulin resistance plays a major role in the development of type 2 diabetes and may be causally associated with increased intracellular fat content. Transgenic mice with adipocyte-specific overexpression of FOXC2 (forkhead transcription factor) have been generated and shown to be protected against diet-induced obesity and glucose intolerance. To understand the underlying mechanism, we examined the effects of chronic high-fat feeding on tissue-specific insulin action and glucose metabolism in the FOXC2 transgenic (Tg) mice. Whole-body fat mass were significantly reduced in the FOXC2 Tg mice fed normal diet or high-fat diet compared with the wild-type mice. Diet-induced insulin resistance in skeletal muscle of the wild-type mice was associated with defects in insulin signaling and significant increases in intramuscular fatty acyl CoA levels. In contrast, FOXC2 Tg mice were completely protected from diet-induced insulin resistance and intramuscular accumulation of fatty acyl CoA. High-fat feeding also blunted insulin-mediated suppression of hepatic glucose production in the wild-type mice, whereas FOXC2 Tg mice were protected from diet-induced hepatic insulin resistance. These findings demonstrate an important role of adipocyte-expressed FOXC2 on whole-body glucose metabolism and further suggest FOXC2 as a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.
authors.affiliation: Yale University School of Medicine, Department of Internal Medicine, Section of EndocrinologyMetabolism, The Anlyan Center, S269C, 300 Cedar St., P.O. Box 208020, New Haven, CT 06520-8020, USA. jason.k.kim@yale.edu
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Anna
authors.initials: A
authors.lastname: Cederberg
authors.forename: Rickard
authors.initials: R
authors.lastname: Westergren
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.forename: Takamasa
authors.initials: T
authors.lastname: Higashimori
authors.forename: You-Ree
authors.initials: YR
authors.lastname: Cho
authors.forename: Zhen-Xiang
authors.initials: ZX
authors.lastname: Liu
authors.forename: Jianying
authors.initials: J
authors.lastname: Dong
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Sven
authors.initials: S
authors.lastname: Enerback
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004041:Dietary Fats / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D000214:Acyl Coenzyme A; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; D007328:Insulin; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein