Effect of High Fat Diet on Hindbrain Prolactin-Releasing Peptide Neurons and Satiety

[摘要] Rats fed high fat diet (HFD) eat larger meals compared to chow-fed rats before the onset of obesity, suggesting a reduced sensitivity to endogenous satiety signals (e.g., cholecystokinin (CCK)). CCK is released in response to nutrient absorption at the proximal small intestine and activates CCK receptors expressed on vagal afferents innervating gut mucosa, which then relay signals to the nucleus of the solitary tract (NTS), the site where vagal afferents terminate. Within the caudal NTS (cNTS), the A2 noradrenergic (NA) neuronal population is important for the regulation of food intake. Lesions of hindbrain A2 NA neurons eliminate the intake suppressive effects of CCK, suggesting that they play an important role in relaying satiety signals arising from the gut. A subset of A2 NA neurons is positive for prolactin-releasing peptide (PrRP), which suppresses food intake and body weight. This study investigates the effects of acute and chronic (2 and 7 weeks, respectively) HFD maintenance on the activation of hindbrain PrRP+ neurons and satiety. We tested the hypotheses that exposure to HFD blunts the ability of CCK to recruit PrRP neurons in the cNTS (experiment 1), and that chronic HFD exposure attenuates CCK’s satiating effects by reducing recruitment of PrRP neurons in the cNTS (experiment 2). Both acute and chronic HFD-fed rats consumed significantly more calories and gained more weight compared to chow-fed rats. In experiment 2, behavioral testing revealed a trend towards an attenuation of CCK’s intake suppressive effects in HFD-fed compared to chow-fed rats after 1 week and 6 weeks of diet exposure. Finally, after 2 or 7 weeks, animals were sacrificed after injections of saline (2mL), 1μg/kg or 5μg/kg CCK, or no injection and brains were assessed for cFos and PrRP immunolabeling. Our data provide evidence that after chronic HFD maintenance, PrRP+ neuronal signaling at the level of the NTS is implicated, suggesting that the activity of the PrRP+ population is impaired and contributes to the hyperphagia and increased weight gain observed in the rats fed HFD.

[发布机构] the University of Pittsburgh