title: Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats.
abstract: Adiponectin (Acrp30) is a physiologically active polypeptide hormone secreted by adipose tissue that shows insulin-sensitizing, antiinflammatory, and antiatherogenic properties. In humans, Acrp30 levels are inversely related to the degree of adiposity. In the current study, we tested the long-term weight-reducing and insulin-enhancing effects of Acrp30 cDNA delivered peripherally by a viral vector. To this end, we have generated a series of recombinant adeno-associated virus vectors of serotypes 1 and 5 encoding mouse Acrp30 cDNAs. The long-term expression of recombinant adeno-associated virus-Acrp30 vectors was tested after intramuscular or intraportal injection in female Sprague-Dawley rats with diet-induced obesity. We show that a single peripheral injection of 10(12) physical particles of Acrp30-encoding vectors resulted in sustained (up to 280 days) significant reduction in body weight, concomitant with the reduction in daily food intake. Acrp30 treatment resulted in higher peripheral insulin sensitivity measured by the i.p. glucose tolerance test in fasted animals. Ectopic expression of the Acrp30 transgene resulted in modulation of hepatic gluconeogenesis and lipogenesis, as demonstrated by the reduction of the expression of two key genes: PEPCK (phosphoenolpyruvate carboxykinase) and SREBP-1c (sterol regulatory element-binding protein 1c) in the liver. These data show successful peripheral therapy in a clinically relevant model for human obesity and insulin resistance.
authors: Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610-0266, USA.
authors: Stanislav
authors: S
authors: Shklyaev
authors: George
authors: G
authors: Aslanidi
authors: Michael
authors: M
authors: Tennant
authors: Victor
authors: V
authors: Prima
authors: Eric
authors: E
authors: Kohlbrenner
authors: Vadim
authors: V
authors: Kroutov
authors: Martha
authors: M
authors: Campbell-Thompson
authors: James
authors: J
authors: Crawford
authors: Eugene W
authors: EW
authors: Shek
authors: Philip J
authors: PJ
authors: Scarpace
authors: Sergei
authors: S
authors: Zolotukhin
mesh_terms: D052242:Adiponectin; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001835:Body Weight; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004435:Eating; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D005943:Gluconeogenesis; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
chemical_list: D052242:Adiponectin; D022762:CCAAT-Enhancer-Binding Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; D011506:Proteins; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases