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

Abstract

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.

Fig. 1.

Changes in body weight (A), body composition including fat (B), fluid (C), lean (D), serum leptin (E), and cumulative food intake (F) over 24-wk in control (fructose-free)-fed and 60% fructose-fed Sprague Dawley rats. Values are means ± SE of 11 fructose-free and 12 high-fructose-fed rats.

Fig. 2.

Leptin responsiveness as measured by cumulative food intake 24 h after an injection of either saline or 0.6 mg/kg ip leptin prior to initiating the experimental diets (A) and after 6 mo on either the fructose-free control or 60% fructose diet (B). Values represent the means ± SE of 6 fructose-free and 6 high-fructose-fed rats. A: *P = 0.03 for difference with leptin administration by paired t-test. B: **P < 0.04 for difference with leptin; P < 0.02 for difference with diet; and P < 0.04 for interaction by 2-way ANOVA with repeated measures. P = 0.02 for difference with leptin among the control animals by post hoc analysis.

Fig. 3.

Hypothalamic protein levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3; A) and leptin receptor (B) in fructose-free control and 60% fructose-fed rats. Values represent the means ± SE of 5 fructose-free- and 6 high-fructose-fed rats. *P = 0.015 for difference with high-fructose feeding by t-test.

Fig. 4.

Food intake (A) and change in body weight (B) in rats either maintained on the fructose-free (control; n = 5) or high-fructose diets (n = 6) or switched from the control to high-fat diet (n = 6) or from high-fructose to high-fat (n = 6) diets. Values represent the means ± SE. *P < 0.01 for difference with high-fat diet by t-test at individual days. Note that several assessments were performed on the rats during the 2nd week of high-fat feeding, including fasting prior to blood collection, which disturbed normal food intake and body weight.