Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

Abstract

Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by upregulating BDNF.

Novel common copy number variation for early onset extreme obesity on chromosome 11q11 identified by a genome-wide analysis

“…Additionally, within the 20 associated regions, we confirmed two previously published obesity associations: CNVR 1p31.1 20 kb upstream of NEGR1 (7,8) and CNVR 10q11.22 (1) covering the four genes SYT15 , GPRIN2 , LOC728643 and PPYR1 (19) with PPYR1 being the most interesting candidate, given its role in energy homeostasis and regulation of food intake (27,32). PPYR1 null animals have, for instance, a reduced body weight.…”

“…PP reduces food intake predominantly via stimulation of the anorexigenic melanocortinergic pathway. This effect is mediated by direct action on local PPYR1 within the arcuate nucleus (32). PP binds to the PPYR1.…”

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

“…Studies have shown that the Y4 receptor is involved in the regulation of feeding [66, 67], circadian ingestion and energy homeostasis [68] and colonic muscle contraction [69]. The human Y4 receptor also plays a critical role in the regulation of food intake and reproductive functions [70].…”

Appetite regulation and weight control: the role of gut hormones

“…97 Despite its demonstrated anorexigenic effects and its possible anti-obesity utility, the exact hypothalamic nuclei and downstream pathways through which PP Y4 agonism functions to regulate food intake and body weight have, however, yet to be fully elucidated. 99 A recent study in mice has demonstrated the peripheral PP-mediated suppression of orexigenic pathways in the lateral hypothalamic area, or ‘feeding centre', and upregulation of anorexigenic pathways in the ventromedial hypothalamus, or ‘satiety centre'. 99 These effects were shown to be mediated via the Y4 receptor, as they were not reproducible in Y4 receptor knockout mice.…”