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Am J Physiol Regul Integr Comp Physiol (August 13, 2008). doi:10.1152/ajpregu.00195.2008
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Submitted on March 17, 2008
Accepted on August 7, 2008

Fructose-Induced Leptin Resistance Exacerbates Weight Gain in Response to Subsequent High Fat Feeding

Alexandra Shapiro1*, Wei Mu2, Carlos A Roncal2, Kit-Yan Cheng3, Richard J. Johnson2, and Philip J. Scarpace3

1 Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States
2 Nephrology, University of Florida, Gainesville, Florida, United States
3 Dept. of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida, United States

* To whom correspondence should be addressed. E-mail: sasha1{at}ufl.edu.

It has been suggested that increased fructose intake is associated with obesity. We hypothesized that chronic fructose consumption causes leptin resistance, which subsequently may promote the development of obesity in response to a high fat diet. Sprague-Dawley rats were fed a fructose-free control or 60% fructose diet for six months and then tested for leptin resistance. Half of the rats in each group were then switched to high fat diet for two weeks, while the other half continued on their respective diets. Chronic fructose consumption caused leptin resistance while serum leptin levels, weight and adiposity were the same as in control rats that were leptin responsive. Intraperitoneal leptin injections reduced 24-hour food intake in fructose-free group (73.7 ± 6.3 vs 58.1 ± 8 kcal, p=0.02), but had no effect in fructose-fed rats (71.2 ± 6.6 vs 72.4 ± 6.4 kcal, p=0.9). Absence of anorexic response to intraperitoneal leptin injection was associated with 25.7% decrease in hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation in the high-fructose fed rats compared with controls (p=0.015). Subsequent exposure of the fructose-mediated leptin-resistant rats to a high fat diet lead to exacerbated weight gain (50.2 ± 2 g) compared with correspondingly fed leptin-responsive animals that were pre-treated with the fructose-free diet (30.4 ± 5.8 g, p= 0.012). Our data indicate that chronic fructose consumption induces leptin resistance prior to body weight, adiposity, serum leptin, insulin or glucose increases, and this fructose-induced leptin resistance accelerates high fat induced obesity.




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