Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats

Guillaume de Lartigue, Claire Barbier de la Serre, Elvis Espero, Jennifer Lee, Helen E Raybould

Research output: Contribution to journalArticle

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Abstract

Background and Aims: The gastrointestinal hormone cholecystokinin (CCK) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN). Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1) dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation. Results: Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p.), while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid receptor (CB1). In VAN from diet-induced obese (DIO) Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats. Conclusions: Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding, the onset of leptin resistance reduces the sensitivity of VAN to CCK thus reducing the satiating effects of CCK.

Original languageEnglish (US)
Article numbere32967
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 7 2012

Fingerprint

Satiation
Afferent Neurons
cholecystokinin
sensory neurons
Cholecystokinin
Nutrition
satiety
Leptin
leptin
Neurons
Rats
Diet
rats
diet
Zucker Rats
receptors
Eating
melanin
concentrating
food intake

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. / de Lartigue, Guillaume; Barbier de la Serre, Claire; Espero, Elvis; Lee, Jennifer; Raybould, Helen E.

In: PLoS One, Vol. 7, No. 3, e32967, 07.03.2012.

Research output: Contribution to journalArticle

de Lartigue, Guillaume ; Barbier de la Serre, Claire ; Espero, Elvis ; Lee, Jennifer ; Raybould, Helen E. / Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. In: PLoS One. 2012 ; Vol. 7, No. 3.
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