Reversing adipocyte differentiation: implications for treatment of obesity.
Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketotic fat loss that persists after hyperleptinemia disappears, whereas pair-fed controls regain their weight in 2 weeks. We report here that the hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype.
Gifford Laboratories, Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Y T
YT
Zhou
Z W
ZW
Wang
M
M
Higa
C B
CB
Newgard
R H
RH
Unger
D000256:Adenoviridae; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D001833:Body Temperature Regulation; D002454:Cell Differentiation; D003587:Cytomegalovirus; D003920:Diabetes Mellitus / Q000473:pathology / Q000628:therapy*; D004822:Epididymis; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D020738:Leptin; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D009765:Obesity / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
D020738:Leptin; D008055:Lipids; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D014280:Triglycerides