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

• Published in: PloS one Vol. 7; no. 3; p. e32967
• Main Authors: de Lartigue, Guillaume, Barbier de la Serre, Claire, Espero, Elvis, Lee, Jennifer, Raybould, Helen E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.03.2012; Public Library of Science (PLoS)
• Subjects: Amphetamines; Anatomy & physiology; Animals; Biology; Body Weight; Cannabinoid CB1 receptors; Cells, Cultured; Cholecystokinin; Cholecystokinin - metabolism; Cholecystokinin - pharmacology; Cocaine; Diet; Diet, High-Fat; Down-regulation; Eating; EGR-1 protein; Food; Food intake; Genotype & phenotype; High fat diet; Hyperphagia; Ingestion; Insulin resistance; Leptin; Leptin - metabolism; Leptin - pharmacology; Male; Medicine; Melanin; Melanin-concentrating hormone; Neurons; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Neuropeptides; Obesity; Obesity - etiology; Peptides; Phenotype; Physiology; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors; Rodents; Satiation - drug effects; Satiety; Sensitivity; Sensory neurons; Signal Transduction - drug effects; Signaling; Vagus nerve; Vagus Nerve - drug effects; Vagus Nerve - metabolism; Veterinary colleges; Veterinary medicine; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0032967

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. 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. 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.