TY - JOUR
T1 - Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity
AU - Lodhi, Irfan J.
AU - Yin, Li
AU - Jensen-Urstad, Anne P.L.
AU - Funai, Katsuhiko
AU - Coleman, Trey
AU - Baird, John H.
AU - El Ramahi, Meral K.
AU - Razani, Babak
AU - Song, Haowei
AU - Fu-Hsu, Fong
AU - Turk, John
AU - Semenkovich, Clay F.
N1 - Funding Information:
This work was supported by NIH grants DK088083, DK076729, F32 DK083895, KO8 HL098559, DK20579, DK56341, DK34388, RR00954, and T32 DK07120. Alan Bohrer provided mass spectrometry expertise.
PY - 2012/8/8
Y1 - 2012/8/8
N2 - De novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPARγ) modulates endogenous PPARγ activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPARγ transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPARγ and treatment of 3T3-L1 cells with one such ether lipid increased PPARγ transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPARγ transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPARγ-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
AB - De novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPARγ) modulates endogenous PPARγ activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPARγ transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPARγ and treatment of 3T3-L1 cells with one such ether lipid increased PPARγ transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPARγ transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPARγ-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
UR - http://www.scopus.com/inward/record.url?scp=84864705801&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2012.06.013
DO - 10.1016/j.cmet.2012.06.013
M3 - Article
C2 - 22863804
AN - SCOPUS:84864705801
SN - 1550-4131
VL - 16
SP - 189
EP - 201
JO - Cell metabolism
JF - Cell metabolism
IS - 2
ER -