Forkhead Transcription Factor FoxO1 in Adipose Tissue Regulates Energy Storage and Expenditure

Forkhead Transcription Factor FoxO1 in Adipose Tissue Regulates Energy Storage and Expenditure Jun Nakae 1 , Yongheng Cao 1 , Miyo Oki 1 , Yasuko Orba 2 , Hirofumi Sawa 3 , Hiroshi Kiyonari 4 , Kristy Iskandar 5 , Koji Suga 1 , Marc Lombes 6 and Yoshitake Hayashi 5 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 Abstract 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 [aP 2 ]-FLAG-Δ256) using an aP 2 promoter/enhancer and a mutant FoxO1 (FLAGΔ256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAGΔ256 on glucose metabolism and energy homeostasis. RESULTS —The aP 2 -FLAG-Δ256 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 α (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white a