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This Article Full Text Full Text (PDF) Supplemental Table and Figure All Versions of this Article: 293/3/E726    most recent 00248.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Aslanidi, G. Articles by Zolotukhin, S. Search for Related Content PubMed PubMed Citation Articles by Aslanidi, G. Articles by Zolotukhin, S.

Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats

¹Department of Pediatrics, ²Department of Pathology, ³Department of Physiology and Functional Genomics, ⁴Department of Surgery, and ⁵Department of Physiological Sciences, University of Florida, Gainesville, Florida; and ⁶Department of Molecular and Integrative Physiology and ⁷Orthopaedic Research Labs, University of Michigan Medical School, Ann Arbor, Michigan

Submitted 22 April 2007 ; accepted in final form 15 June 2007

The Wnt family of secreted glycoproteins had previously been shown to regulate diverse processes during early development. Wnt signaling also plays a key role in the homeostasis of adult tissues maintaining stem cell pluripotency and determining differentiating cell fate. The age-related decrease in Wnt signaling may contribute to increased muscle adiposity and diminished bone strength. In the current study, we investigated the long-term metabolic consequences of the upregulated Wnt/-catenin signaling in skeletal muscles of adult diet-induced obese (DIO) rats. To this end, we generated a recombinant adeno-associated virus (rAAV) vector encoding murine Wnt10b cDNA. The long-term expression of rAAV1-Wnt10b was tested after intramuscular injection in the female DIO rat. Animals fed high-fat diet and treated with rAAV1-Wnt10b showed a sustained reduction in body weight compared with controls, and expression of Wnt10b was accompanied by a reduction in hyperinsulinemia and triglyceride plasma levels as well as improved glucose homeostasis. Nuclear magnetic resonance methods revealed that ectopic expression of Wnt10b resulted in a decrease in both global and muscular fat deposits in DIO rats. The long-range effect of locally expressed Wnt10b was also manifested through the increased bone mineral density. The detailed analysis of molecular markers revealed fibroblast growth factor-4 and vascular endothelial growth factor as possible mediators of the systemic effect of Wnt10b transgene expression. Our data demonstrate that altering Wnt/-catenin signaling in the skeletal muscle of an adult animal invokes moderate responses with favorable metabolic profile, bringing the notion of alternative therapeutic modality in the treatment of obesity, diabetes, and osteoporosis.

Wnt10b; gene therapy; obesity; diabetes