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Submitted on June 30, 2003
Accepted on December 11, 2003
1 Department of Medicine, University of Utah, 50 N. Medical Dr., Salt Lake City, UT 84132; VA Medical Center, Salt Lake City, UT 84132; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216; Cardiovascular and Metabolic Diseases, Pharmacia Corporation, St. Louis, MO 63167
* To whom correspondence should be addressed. E-mail: donald.mcclain{at}hsc.utah.edu.
Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine: fructose-6-phosphate amidotransferase, GFA) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed GFA 2.5-fold specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and betahydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-D-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNF
and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and PPAR
decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that has been refed for 6 h after a 24 h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.
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