Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats

^*Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, and Departments of ^†Pathology and ^‡Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610-0266; and ^§Malcolm Randall Department of Veterans Affairs Medical Center, Gainesville, FL 32608-1135

Edited by Kenneth I. Berns, University of Florida, Gainesville, FL, and approved September 17, 2003 (received for review June 24, 2003)

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 10¹² 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.

Footnotes

↵ ¶ To whom correspondence should be addressed at: P.O. Box 100266, Powell Gene Therapy Center, J. Hillis Miller Health Center, University of Florida, Gainesville, FL 32610-0266. E-mail: sergei{at}ufl.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Acrp30, adiponectin; AMPK, AMP-activated protein kinase; BW, body weight; DIO, diet-induced obesity; FE, feed efficiency; FI, food intake; GT, glucose tolerance; HF, high-fat diet; IP GTT, i.p. GT test; ND, normal diet; PEPCK, phosphoenolpyruvate carboxykinase; PVI, portal-vein injection; rAAV, recombinant adeno-associated viral; RQ, relative quantitative.