Zfp238 Regulates the Thermogenic Program in Cooperation with Foxo1
Motoko Kita,
Jun Nakae,
Yoshinaga Kawano,
Hiroshi Asahara,
Hiroshi Takemori,
Haruo Okado,
Hiroshi Itoh
Affiliations
Motoko Kita
Navigation Medicine of Kidney and Metabolism, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Jun Nakae
Navigation Medicine of Kidney and Metabolism, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Physiology, International University of Health and Welfare School of Medicine, Narita 286-8686, Japan; Corresponding author
Yoshinaga Kawano
Navigation Medicine of Kidney and Metabolism, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Hiroshi Asahara
Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Hiroshi Takemori
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
Haruo Okado
Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-0057, Japan
Hiroshi Itoh
Navigation Medicine of Kidney and Metabolism, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Summary: Obesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO) in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1. : Molecular Interaction; Molecular Mechanism of Behavior; Diabetology; Specialized Functions of Cells Subject Areas: Molecular Interaction, Molecular Mechanism of Behavior, Diabetology, Specialized Functions of Cells
