Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance.
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.
Kim
Jason K
JK
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
Kim
Hyo-Jeong
HJ
Park
So-Young
SY
Cederberg
Anna
A
Westergren
Rickard
R
Nilsson
Daniel
D
Higashimori
Takamasa
T
Cho
You-Ree
YR
Liu
Zhen-Xiang
ZX
Dong
Jianying
J
Cline
Gary W
GW
Enerback
Sven
S
Shulman
Gerald I
GI
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*
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