Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content

Br J Nutr. 2011 Aug;106(3):390-7. doi: 10.1017/S000711451100033X. Epub 2011 Mar 22.


Chronic consumption of a Western-type diet, containing both elevated sugar and fat, results in leptin resistance. We hypothesised that fructose, as part of the sugar component of Western-type diets, is one causative ingredient in the development of leptin resistance and that removal of this component will prevent leptin resistance despite high fat (HF) content. We fed rats a sugar-free (SF), 30 % HF (SF/HF) diet or a 40 % high-fructose (HFr), 30 % HF (HFr/HF) diet for 134 d. The HFr/HF diet resulted in impaired anorexic and body-weight responses to both peripherally (0·6 mg/kg, assessed on day 65 of the diet) and centrally (1·5 μg/d, assessed on days 129-134) administered leptin, whereas SF/HF-fed rats were fully leptin responsive. At day 70, half the HFr/HF-fed animals were switched to the SF/HF diet, reversing the leptin resistance (assessed 18 d after the diet switch). The HFr/HF diet elevated serum leptin and reduced adiponectin, and levels were restored abruptly at day 3 after switching to the SF/HF diet. These data demonstrate that a diet containing both HFr and fat leads to leptin resistance, while an isoenergetic SF/HF diet does not. Moreover, removal of fructose from this diet reverses the leptin resistance and the elevated leptin, suggesting a cause-and-effect relationship. These data suggest that fructose is the bioactive component of a HF/high-sugar diet that is essential for the induction of leptin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood
  • Animals
  • Anorexia / etiology
  • Appetite / drug effects*
  • Body Weight / drug effects*
  • Dietary Fats / administration & dosage*
  • Dietary Fats / adverse effects
  • Dietary Sucrose / adverse effects*
  • Fructose / adverse effects*
  • Leptin / metabolism*
  • Male
  • Metabolic Diseases / blood
  • Metabolic Diseases / drug therapy*
  • Metabolic Diseases / prevention & control
  • Rats
  • Rats, Sprague-Dawley


  • Adiponectin
  • Dietary Fats
  • Dietary Sucrose
  • Leptin
  • Fructose