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Forkhead transcription factor FoxO1 in adipose tissues regulates energy storage and expenditure

¹ 21st Century COE Program for Signal Transduction Disease: Diabetes Mellitus as Model, Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Disease, Kobe University Graduate school of Medicine, Kobe 650-0017, Japan
² Laboratory of Molecular & Cellular Pathology, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan
³ 21st Century COE Program for Zoonosis Control, Department of Molecular Pathobiology, Hokkaido University Research Center for Zoonosis Control, N18, W9, Kita-ku, Sapporo 060-0818, Japan
⁴ Laboratory for Animal Resources and Genetics Engineering Team, RIKEN Center for Developmental Biology (CDB), 2-2-3 Minatojima-minami-cho, Chuou-ku Kobe, Hyogo 650-0047, Japan
⁵ Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment (ICMRT), Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
⁶ INSERM U 693, Faculte de Medecine Paris-Sud, 63, rue Gabriel Peri, 94276 Le Kremlin Bicêtre Cedex, France

Objective: Adipose tissues serve as integrators of various physiological pathways, energy balance and glucose homeostasis. Forkhead transcription factor FoxO (Forkhead bOX-containing protein O subfamily) 1 mediates insulin action at transcriptional level. However, physiological roles of FoxO1 in adipose tissues remain unclear.

Research Design and Methods: In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (aP₂-FLAG-256) using adipose-specific adipocyte protein 2 (aP₂) promoter/enhancer and a mutant FoxO1 (FLAG256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed effects of overexpression of the FLAG256 on glucose metabolism and energy homeostasis.

Results: The aP₂-FLAG-256 showed improved glucose tolerance and insulin sensitivity accompanied with smaller size of adipocytes and increased Adiponectin (Adipoq) and Glut 4 (Slc2a4) and decreased Tnf (Tnf) and Ccr2 (Ccr2) gene expression levels in white adipose tissue (WAT) under high fat diet. Furthermore, the aP₂-FLAG-256 had increased oxygen consumption accompanied with increased expression of PGC-1 protein and Ucp-1 (Ucp1), Ucp-2 (Ucp2), and β3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of the FLAG256 in T37i cells, which are derived from hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1 protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1 (Ppargc1a), Pgc1β (Ppargc1b), Ucp1 and Adrb3 gene expression.

Conclusions: These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake.

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