Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats.
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.
Shklyaev
Stanislav
S
Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610-0266, USA.
Aslanidi
George
G
Tennant
Michael
M
Prima
Victor
V
Kohlbrenner
Eric
E
Kroutov
Vadim
V
Campbell-Thompson
Martha
M
Crawford
James
J
Shek
Eugene W
EW
Scarpace
Philip J
PJ
Zolotukhin
Sergei
S
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
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