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

doi:10.2337/db07-0698

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

¹21st 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
²Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
³21st Century COE Program for Zoonosis Control, Department of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
⁴Laboratory for Animal Resources and Genetics Engineering Team, RIKEN Center for Developmental Biology, Hyogo, Japan
⁵Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment, Kobe University Graduate School of Medicine, Kobe, Japan
⁶Institut 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 [aP₂]-FLAG-Δ256) using an aP₂ 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 aP₂-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 adipose tissue (WAT) under a high-fat diet. Furthermore, the aP₂-FLAG-Δ256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and β3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAGΔ256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1α protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1α (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.

Footnotes

Published ahead of print at http://diabetes.diabetesjournals.org on 27 December 2007. DOI: 10.2337/db07-0698.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0698.

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- Received May 26, 2007.
- Accepted December 12, 2007.