An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis.

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.

Prolactin-releasing peptide increases food intake and affects hypothalamic physiology in Japanese quail (Coturnix japonica).

Prolactin-releasing peptide (PrRP) increases food intake in birds, whereas it is a potent satiety factor in rodents and fish. The aim of this study was to determine the effects of central injection of PrRP on feeding behaviors and hypothalamic physiology in juvenile Japanese quail (Coturnix japonica). Intracerebroventricular injection of 1,692 pmol of PrRP increased food intake for the first 90 min after injection but did not affect water intake. Quail treated with PrRP displayed more food and drink pecks, less time standing but more perching, and decreased defecations. Prolactin-releasing peptide-injected quail had increased c-Fos immunoreactivity in the dorsomedial nucleus (DMN) and arcuate nucleus (ARC) of the hypothalamus. Hypothalamic neuropeptide Y receptor subtypes 2 and 5 and melanocortin receptor 4 mRNAs were greater in PrRP- than vehicle-injected quail. In the DMN, there was less corticotropin-releasing factor (CRF) mRNA and in the ARC, more CRF mRNA in PrRP- than vehicle-injected chicks. Thus, PrRP increases food intake in quail, which is associated with changes in hypothalamic CRF and neuropeptide Y receptor gene expression and c-Fos-immunolabeled cells in the ARC and DMN.

Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob/ob mice.

Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm11-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm11-PrRP31 (5 mg/kg) and leptin (5 or 10 µg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm11-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm11-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm11-PrRP31, and their combination. Thus, palm11-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm11-PrRP31 analog.

Repeated peripheral administration of lipidized prolactin-releasing peptide analog induces c-fos and FosB expression in neurons of dorsomedial hypothalamic nucleus in male C57 mice.

Previous studies indicate that hypothalamic prolactin-releasing peptide (PrRP), signaling via GPR10 and neuropeptide FF2 receptor, is involved in energy homeostasis, stress responses, and cardiovascular regulation. Energy homeostasis depends on the balance between food intake regulation and energy expenditure, in which the hypothalamus plays a key role. The lipidization of PrRP31 with palmitoyl acid allows it to produce its anorexigenic effect after repeated peripheral administration and to reduce body weight and improve metabolic parameters in diet-induced obese (DIO) mice. The aim of this study was to reveal the transient and long-lasting changes in neuronal activity via c-Fos and FosB immunohistochemistry in brain nuclei related to food intake regulation and energy homeostasis during the first days of treatment with a newly designed lipidized analog of PrRP31 (palm11-PrRP31) with promising antiobesity effects. The data revealed that the anorexigenic effect of repeated application of palm11-PrRP31 was associated with delayed but gradually significantly reduced cumulative food intake in mice as well as with a significant reduction in their body weight. Moreover, while the repeated application of palm11-PrRP31 was associated with a significant reduction in acute cell activity in the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS) compare to its acute treatment, both acute and long-lasting cell activity in the dorsomedial hypothalamic nucleus (DMN) were increased. The data indicate that DMN neurons might be tonically activated after repeated administration of lipidized PrRP analogs that may be associated with the process of long-term adaptation to modified energy homeostasis.

Dietary Macronutrient Composition Affects the Influence of Exogenous Prolactin-Releasing Peptide on Appetite Responses and Hypothalamic Gene Expression in Chickens.

BACKGROUND: The interaction between the effects of exogenous neurotransmitters and dietary composition on appetite regulation in nonmammalian species is unclear. OBJECTIVE: The objective of this study was to determine the effects of exogenous prolactin-releasing peptide (PrRP) and dietary macronutrient composition on food intake regulation in broiler chicks. METHODS: Three isocaloric diets were formulated: high-carbohydrate (HC), high-fat (HF; 60% of ME from lard) and high-protein (HP) diets. In Expt. 1, 4-d-old Hubbard × Cobb-500 chicks fed 1 of the 3 diets since hatch were intracerebroventricularly injected with 0 (vehicle), 3, or 188 pmol PrRP (n = 10). Food intake was measured for 180 min. In Expt. 2, hypothalamic mRNA abundance of appetite-associated factors was measured in hypothalamus samples obtained 1 h postinjection of 0 or 188 pmol PrRP. In Expt. 3, chicks were given free access to all diets before and after intracerebroventricular injection and food intake was measured. RESULTS: Three and 188 pmol PrRP increased (P = 0.0008 and 0.04) HP diet intake, but only 188 pmol PrRP was efficacious at increasing HC (P = 0.0011) and HF (P = 0.01) consumption compared with the vehicle. There was a diet effect on mRNA abundance of all genes (P < 0.05), with greater expression in chicks fed the HF or HP than the HC diet. Whereas neuropeptide Y (NPY) mRNA was similar between vehicle- and PrRP-injected chicks that consumed HP or HF diets, expression was greater (P < 0.05) in PrRP- than vehicle-injected chicks that consumed the HC diet. When chicks had access to all diets, 188 pmol PrRP caused preferential (P < 0.0001) intake of the HP over the HC and HF diets. CONCLUSION: The HP diet enhanced the sensitivity of chicks to the food intake-stimulating effects of PrRP, and PrRP in turn increased preference for the HP diet. Thus, dietary macronutrient composition influences PrRP-mediated food intake, and PrRP in turn affects nutrient intake and transcriptional regulation in chicks.

Peripheral administration of palmitoylated prolactin-releasing peptide induces Fos expression in hypothalamic neurons involved in energy homeostasis in NMRI male mice.

Energy homeostasis is the result of a balance between energy intake and expenditure, and the hypothalamus plays a key role in the regulation of these processes. The hypothalamic prolactin-releasing peptide (PrRP) is involved in food intake regulation and energy homeostasis, although only its lipidized analogs exert central anorexigenic effects after peripheral administration. The aim of the present study was to delineate the extent of the Fos expression as a marker of neuronal activation within the hypothalamic structures involved in food intake regulation after peripherally administered palmitoylated PrRP31 (palm-PrRP31) and to determine whether the anorexigenic effect of peripherally administered palm-PrRP31 influence the activity of hypocretin (HCRT) and oxytocin (OXY) neurons, i.e., the neuropeptides crucially involved in the regulation of energy homeostasis. The data confirmed an anorexigenic effect of palm-PrRP31 treatment (5mg/kg, s.c.) in mice. In the palm-PrRP31-treated animals, a significant increase in Fos expression was observed in the hypothalamic paraventricular (PVN), dorsomedial (DMN), and arcuate (Arc) nuclei and in the neurons of the nucleus of the solitary tract (NTS). Moreover, significant Fos expression was observed in the lateral hypothalamic area (LHA) HCRT neurons and PVN OXY neurons after palm-PrRP31 administration. The present findings may indicate that palm-PrRP31 may be involved in energy homeostasis via the activation of several hypothalamic structures. Fos activation of the hypothalamic OXY and HCRT neurons in the PVN and LHA emphasizes the importance of the areas mentioned in the central action of palm-PrRP31.

Effect of oxytocin, prolactin-releasing peptide, or corticotropin-releasing hormone on feeding behavior in steers.

As a preliminary step to elucidate the involvement of central neurotransmitters in the dip in voluntary feed intake during the perinatal period in cows, we investigated the effect of intracerebroventricular (ICV) administration of oxytocin, prolactin-releasing peptide (PrRP), or corticotropin-releasing hormone (CRH), the central functions of all of which undergo drastic changes during the perinatal period, on feed intake in steers. Thirty minutes before the onset of feeding, the treatment solution was injected into the third ventricle through an implanted cannula, and feeding-related behaviors were observed for 1 h after the onset of feeding. Neither ICV oxytocin (5 and 50 µg) nor PrRP (2 and 20 nmol) reduced feed intake (n=6). Twenty nanomoles of bovine CRH noticeably inhibited feeding behavior compared with vehicle treatment (n=5, p<0.05). Fifty micrograms of oxytocin reduced latency to the first water access after feeding onset (p<0.1), which may be because of the stimulation of arginine vasopressin V1b receptor by the high dose of oxytocin. We conclude that CRH inhibits feeding behavior by its central action in this species, although this could also be an indirect effect due to the increased expression of abnormal behaviors caused by CRH. Central administration of neither oxytocin nor PrRP reduced feed intake in steers. Although the effects of sex steroids need to be examined, it appears that increased activity of oxytocin, and possibly PrRP, during the perinatal period does not contribute to the dip in voluntary feed intake in this species. On the other hand, it makes sense that suppressed central CRH activity during the perinatal period should act in the direction of maintaining or even increasing food intake to aid a steady supply of energy to the fetus or offspring. We thus speculate that CRH is not a prime candidate involved in the dip in voluntary feed intake during the perinatal period in cows.