Reversing adipocyte differentiation: implications for treatment of obesity

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.2391-2395
• Main Authors: Zhou, Y.T. (University of Texas, Dallas.), Wang, Z.W, Higa, M, Newgard, C.B, Unger, R.H
• Format: Article
• Language: English
• Subjects: ACIDE GRAS; ACIDOS GRASOS; Adenoviridae; Adenovirus; Adenoviruses; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipocytes - pathology; Adipose Tissue - pathology; ADIPOSE TISSUES; ADN; ANIMAL TRANSGENIQUE; ANIMALES TRANSGENICOS; Animals; Biological Sciences; BODY FAT; Body Temperature Regulation; CELL DEDIFFERENTIATION; CELL DIFFERENTIATION; CELLS; CELLULE; CELULAS; COMPLEMENTARY DNA; CONTROL HORMONAL; CONTROLE HORMONAL; Cytomegalovirus; Diabetes; Diabetes Mellitus - pathology; Diabetes Mellitus - therapy; DIFERENCIACION CELULAR; DIFFERENCIATION CELLULAIRE; DNA; ENZIMAS; ENZYME; ENZYMES; EPIDIDYMAL FAT PADS; Epididymis; FACTEUR DE TRANSCRIPTION; FACTORES DE TRANSCRIPCION; FATTY ACIDS; Gene Expression Regulation; GENE TRANSFER; Genetic Therapy; GENETIC TRANSFORMATION; Genetic Vectors; HORMONAL CONTROL; HORMONAS; HORMONE; HORMONES; HYPERLEPTINEMIA; LEPTIN; Lipids - biosynthesis; LIPOGENESE; LIPOGENESIS; LIPOLISIS; LIPOLYSE; LIPOLYSIS; Male; Medical research; Messenger RNA; Obesity; Obesity - genetics; Obesity - pathology; Obesity - therapy; OXIDACION; OXIDATION; OXYDATION; PEPTIDE; PEPTIDES; PEPTIDOS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR; POLYPEPTIDES; Protein Biosynthesis; Proteins - genetics; Proteins - therapeutic use; RAT; RATA; RATS; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - genetics; Recombinant Proteins - biosynthesis; Recombinant Proteins - therapeutic use; TEJIDO ADIPOSO; TISSU ADIPEUX; TRANSCRIPTION FACTORS; Transcription Factors - genetics; TRANSFERENCIA DE GENES; TRANSFERT DE GENE; TRANSFORMACION GENETICA; TRANSFORMATION GENETIQUE; TRANSGENIC ANIMALS; Triglycerides; Triglycerides - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.5.2391

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, PPAR alpha, 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