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Published online December 27, 2007
Diabetes 57:563-576, 2008
DOI: 10.2337/db07-0698
© 2008 by the American Diabetes Association
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Forkhead Transcription Factor FoxO1 in Adipose Tissue Regulates Energy Storage and Expenditure

Jun Nakae1, Yongheng Cao1, Miyo Oki1, Yasuko Orba2, Hirofumi Sawa3, Hiroshi Kiyonari4, Kristy Iskandar5, Koji Suga1, Marc Lombes6, and Yoshitake Hayashi5

1 21st Century Center of Excellence (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, Japan
2 Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
3 21st Century COE Program for Zoonosis Control, Department of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
4 Laboratory for Animal Resources and Genetics Engineering Team, RIKEN Center for Developmental Biology, Hyogo, Japan
5 Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment, Kobe University Graduate School of Medicine, Kobe, Japan
6 Institut National de la Santé et de la Recherch Médicale, Faculte de Medecine, Paris, France

Address correspondence and reprint requests to Jun Nakae, MD, Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: nakaej{at}med.kobe-u.ac.jp

Abbreviations: aP2, adipocyte protein 2; BAT, brown adipose tissue; CN, constitutively nuclear; FoxO, forkhead box–containing protein O subfamily; PGC, PPAR {gamma} coactivator; PPAR, peroxisome proliferators–activated receptor; shRNA, short-hairpin RNA; UCP, uncoupling protein; WAT, white adipose tissue

OBJECTIVE—Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box–containing protein O subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear.

RESEARCH DESIGN AND METHODS—In the present study, we generated adipose tissue–specific FoxO1 transgenic mice (adipocyte protein 2 [aP2]-FLAG-{Delta}256) using an aP2 promoter/enhancer and a mutant FoxO1 (FLAG{Delta}256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAG{Delta}256 on glucose metabolism and energy homeostasis.

RESULTS—The aP2-FLAG-{Delta}256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smaller-sized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis factor {alpha} (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP2-FLAG-{Delta}256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator–activated receptor {gamma} coactivator (PGC)-1{alpha} protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and β3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAG{Delta}256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1{alpha} protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1{alpha} (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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