Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2008-11, Vol.295 (5), p.R1370-R1375
• Main Authors: Shapiro, Alexandra, Mu, Wei, Roncal, Carlos, Cheng, Kit-Yan, Johnson, Richard J, Scarpace, Philip J
• Format: Article
• Language: English
• Subjects: Animals; Appetite, Obesity, and Digestion; Blotting, Western; Body Composition - drug effects; Diet; Dietary Fats - pharmacology; Drug Synergism; Fructose - pharmacology; Hypothalamus - drug effects; Hypothalamus - metabolism; Insulin - blood; Leptin - blood; Leptin - physiology; Male; Nutrition; Obesity; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal transduction; Sugar; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - biosynthesis; Suppressor of Cytokine Signaling Proteins - genetics; Sweetening Agents - pharmacology; Weight; Weight Gain - drug effects
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00195.2008

1 Department of Pharmacology and Therapeutics and 2 Division of Nephrology, Hypertension, and Transplantation, University of Florida, College of Medicine, Gainesville, Florida Submitted 17 March 2008 ; accepted in final form 7 August 2008 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 6 mo and then tested for leptin resistance. Half of the rats in each group were then switched to high-fat diet for 2 wk, 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-h food intake in the 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 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 led to exacerbated weight gain (50.2 ± 2 g) compared with correspondingly fed leptin-responsive animals that were pretreated 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. obesity Address for reprint requests and other correspondence: A. Shapiro, Dept. of Pharmacology and Therapeutics, Box 100267, Univ. of Florida, Gainesville, Florida 32610 (e-mail: sasha1{at}ufl.edu )