Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure.
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.


METHODS
In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (adipocyte protein 2 [aP(2)]-FLAG-Delta 256) using an aP(2) 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 aP(2)-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 aP(2)-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 beta 3-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), Pgc1 beta (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.
Nakae
Jun
J
Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. nakaej@med.kobe-u.ac.jp
Cao
Yongheng
Y
Oki
Miyo
M
Orba
Yasuko
Y
Sawa
Hirofumi
H
Kiyonari
Hiroshi
H
Iskandar
Kristy
K
Suga
Koji
K
Lombes
Marc
M
Hayashi
Yoshitake
Y
D052437:Adipocytes, Brown / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001831:Body Temperature; D002460:Cell Line; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse