Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

• Keywords
• leptin resistance, obesity, prolactin-releasing peptide, rodent models, type 2 diabetes,
• Publication type
• Journal Article MeSH
• Review MeSH

Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.

• MeSH
• Appetite Depressants administration & dosage   MeSH
• Hormone Antagonists administration & dosage   MeSH
• Chemokines, CC drug effects   metabolism   MeSH
• Cholecystokinin metabolism   MeSH
• Devazepide administration & dosage   MeSH
• Prolactin-Releasing Hormone administration & dosage   analogs & derivatives   MeSH
• Injections, Intraperitoneal MeSH
• Injections, Subcutaneous MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Paraventricular Hypothalamic Nucleus drug effects   metabolism   MeSH
• Solitary Nucleus drug effects   metabolism   MeSH
• Fasting MeSH
• Peptide Fragments administration & dosage   MeSH
• Eating drug effects   MeSH
• Proto-Oncogene Proteins c-fos metabolism   MeSH
• Signal Transduction MeSH
• Sincalide administration & dosage   analogs & derivatives   MeSH
• Feeding Behavior drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Appetite Depressants MeSH
• Hormone Antagonists MeSH
• Ccl28 protein, mouse MeSH Browser
• Chemokines, CC MeSH
• Cholecystokinin MeSH
• Devazepide MeSH
• Fos protein, mouse MeSH Browser
• Prolactin-Releasing Hormone MeSH
• JMV 236 MeSH Browser
• palm11-PrRP31 MeSH Browser
• Peptide Fragments MeSH
• Proto-Oncogene Proteins c-fos MeSH
• Sincalide MeSH

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) receptor NPFF-R2. The two most potent palmitoylated analogs with anorectic effects in mice, palm11-PrRP31 and palm-PrRP31, were studied in vitro to determine their agonist/antagonist properties and mechanism of action on GPR10, NPFF-R2 and other potential off-target receptors related to energy homeostasis. Palmitoylation of both PrRP31 analogs increased the binding properties of PrRP31 to anorexigenic receptors GPR10 and NPFF-R2 and resulted in a high affinity for another NPFF receptor, NPFF-R1. Moreover, in CHO-K1 cells expressing GPR10, NPFF-R2 or NPFF-R1, palm11-PrRP and palm-PrRP significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and cAMP-responsive element-binding protein (CREB). Palm11-PrRP31, unlike palm-PrRP31, did not activate either c-Jun N-terminal kinase (JNK), p38, c-Jun, c-Fos or CREB pathways in cells expressing NPFF-1R. Palm-PrRP31 also has higher binding affinities for off-target receptors, namely, the ghrelin, opioid (KOR, MOR, DOR and OPR-L1) and neuropeptide Y (Y1, Y2 and Y5) receptors. Palm11-PrRP31 exhibited fewer off-target activities; therefore, it has a higher potential to be used as an anti-obesity drug with anorectic effects.

• Keywords
• GPR10, NPFF-R1, NPFF-R2, binding properties, neuropeptide FF, prolactin-releasing peptide, signaling pathways,
• MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Prolactin-Releasing Hormone chemistry   genetics   metabolism   MeSH
• Cricetinae MeSH
• Humans MeSH
• Lipoylation * MeSH
• Receptors, Neuropeptide genetics   metabolism   MeSH
• Receptors, G-Protein-Coupled genetics   metabolism   MeSH
• In Vitro Techniques MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• neuropeptide FF receptor MeSH Browser
• PRLH protein, human MeSH Browser
• PRLHR protein, human MeSH Browser
• Receptors, Neuropeptide MeSH
• Receptors, G-Protein-Coupled MeSH
• Calcium MeSH

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

• Keywords
• GPR10, RF-amide peptides, energy expenditure, food intake regulation, neuroprotection, prolactin-releasing peptide, signaling,
• MeSH
• Energy Metabolism drug effects   MeSH
• Prolactin-Releasing Hormone chemistry   metabolism   pharmacology   MeSH
• Humans MeSH
• Neurodegenerative Diseases drug therapy   pathology   MeSH
• Neuroprotective Agents chemistry   pharmacology   therapeutic use   MeSH
• Eating drug effects   MeSH
• Receptors, G-Protein-Coupled chemistry   genetics   metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Prolactin-Releasing Hormone MeSH
• Neuroprotective Agents MeSH
• PRLHR protein, human MeSH Browser
• Receptors, G-Protein-Coupled MeSH