Postprandial effects of cholecystokinin are mediated by brainstem PrRP neurons

Amy Worth, Garron Dodd, Nicolas Nunn, Simon Luckman

Research output: Contribution to conferencePoster


Cholecystokinin (CCK) is a gut-hormone, released from the I-cells of the small intestine, with an overarching role in postprandial metabolism. It induces satiation, regulates gastric motility and restrains potentially dangerous excursions in plasma glucose following the ingestion of a meal. CCK acts in a paracrine fashion by binding to CCK1 receptors on sensory vagal afferents, which in turn activate circuits in the brainstem dorsal vagal complex. Our lab has shown previously that central prolactin-releasing peptide (PrRP) regulates food intake and mediates CCK-induced satiety1-3. Furthermore, we have also found that central PrRP reduces gastric motility and plasma glucose, suggesting that it may have an all-encompassing role in mediating the actions of CCK. PrRP is expressed in three discrete areas in the brain: the nucleus of the solitary tract (NTS) and the ventrolateral medulla (VLM) in the brainstem; and dorsomedial nucleus of the hypothalamus (DMN). Using the Cre/loxP system, we genetically dissected the hypothalamic and brainstem neurocircuits by creating a murine knock out of PrRP where expression is selectively rescued in the brainstem alone. The knockout of PrRP (LSL-PrRP) was generated by inserting a loxSTOPlox codon between the PrRP promoter and coding sequence in mice. Immunohistochemistry confirmed the lack of PrRP expression in the brainstem and the hypothalamus. On normal chow, LSL-PrRP mice are significantly heavier than wild-type littermates by 12 weeks of age, and are particularly susceptible to diet-induced obesity, similar to PrRP-/- mice4. Intraperitoneal injection of CCK (10 mg kg-1) significantly decreased food intake in wild-type littermates under nocturnal feeding conditions. In contrast, CCK did not reduce food intake in LSL-PrRP animals. Unlike those in the DMN, PrRP neurons in the brainstem are noradrenergic and express tyrosine hydroxylase (TH). Expression of PrRP in the brainstem, but not the hypothalamus, was rescued by crossing LSL-PrRP mice with TH-Cre mice. This was confirmed by immunohistochemistry. Wild-type and TH-Cre x LSL-PrRP mice respond to intraperitoneal CCK, with a significant reduction in food intake under nocturnal feeding conditions. In contrast, CCK did not reduce food intake in their LSL-PrRP littermates. Therefore, rescue of PrRP in the brainstem alone protects against obesity and restores anorectic responses to CCK. We hypothesize that PrRP acts through its endogenous receptor, GPR10 to affect CCK-induced reductions in gastric motility and plasma glucose. Intracerebroventricular administration of PrRP suppresses the glucose excursion, following an oral glucose load, in wild-type but not GPR10-/- mice. Exogenous PrRP also decreases the rate of gastric emptying, an effect which is blocked with co-administration of a GPR10 receptor antagonist. Thus, PrRP is important in mediating the effects of CCK on inhibiting gastric emptying and food intake, and, may have indirect effects on glucose tolerance. This makes PrRP/GPR10 signaling an attractive anti-obesity candidate that warrants more attention in the understanding of the neural circuitry implicated energy balance. 1. Lawrence, C.B., Celsi, F., Brennand, J. & Luckman, S.M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nature neuroscience 3, 645-646 (2000). 2. Lawrence, C.B., Ellacott, K.L.J. & Luckman, S.M. PRL-releasing peptide reduces food intake and may mediate satiety signaling. Endocrinology 143, 360-367 (2002). 3. Bechtold, D.a. & Luckman, S.M. Prolactin-releasing Peptide mediates cholecystokinin-induced satiety in mice. Endocrinology 147, 4723-4729 (2006). 4. Takayanagi, Y., et al. Endogenous prolactin-releasing peptide regulates food intake in rodents. The Journal of clinical investigation 118, 4014-4024 (2008).
Original languageEnglish
Publication statusPublished - 14 Apr 2013
EventProgramming Obesity: Central and Peripheral Contributors - University of Cambridge, Cambridge, United Kingdom
Duration: 14 Apr 201316 Apr 2013


ConferenceProgramming Obesity: Central and Peripheral Contributors
Country/TerritoryUnited Kingdom


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