Overexpression of the rate-limiting
enzyme for
hexosamine synthesis (
glutamine:fructose-6-phosphate amidotransferase) 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
glutamine:fructose-6-phosphate amidotransferase 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
beta-hydroxybutyrate 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 alpha and
resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of
mRNA for
leptin were increased and
peroxisome proliferator-activated receptor gamma decreased. To further explore the relationship between
adiponectin and
insulin sensitivity, we examined mice that have 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.