Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E187-95. doi: 10.1152/ajpendo.00056.2011. Epub 2011 Apr 26.


Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Diet / adverse effects*
  • Diet, Atherogenic
  • Dietary Fats / pharmacology
  • Drug Resistance* / drug effects
  • Drug Resistance* / physiology
  • Energy Intake / drug effects
  • Energy Intake / physiology
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Lipopolysaccharides / pharmacology
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism*
  • Neurons, Afferent / pathology
  • Obesity / complications*
  • Obesity / etiology*
  • Obesity / metabolism
  • Obesity / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Leptin / metabolism
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Suppressor of Cytokine Signaling Proteins / physiology
  • Vagus Nerve / drug effects
  • Vagus Nerve / metabolism*
  • Vagus Nerve / pathology
  • Vagus Nerve Diseases / etiology
  • Vagus Nerve Diseases / metabolism


  • Dietary Fats
  • Leptin
  • Lipopolysaccharides
  • Receptors, Leptin
  • Socs3 protein, rat
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins