Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity

• Published in: PloS one 2017-08, Vol.12 (8), p.e0183449-e0183449
• Main Authors: Pražienková, Veronika, Holubová, Martina, Pelantová, Helena, Bugáňová, Martina, Pirník, Zdenko, Mikulášková, Barbora, Popelová, Andrea, Blechová, Miroslava, Haluzík, Martin, Železná, Blanka, Kuzma, Marek, Kuneš, Jaroslav, Maletínská, Lenka
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Analogs; Animals; beta-Lactamases - metabolism; Binding, Competitive; Bioavailability; Biochemistry; Biology and Life Sciences; Biomarkers; Brain research; CHO Cells; Cholesterol; Cricetinae; Cricetulus; Diabetes; Diabetes mellitus; Diet; Drug therapy; Drugs; Endocrinology; Energy expenditure; Fatty acids; Genetic aspects; Glutamic acid; Insulin; Leptin; Liver; Male; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Metabolomics; Mice; Mice, Inbred C57BL; N-Terminus; Neuropeptides; Nicotinamide; NMR; Nuclear magnetic resonance; Nuclear Magnetic Resonance, Biomolecular; Obesity; Obesity - etiology; Obesity - metabolism; Organic chemistry; Oxidation; Palmitic acid; Palmitoylation; Peptides; Peptides - chemistry; Peptides - pharmacology; Physiological aspects; Physiology; Plasma levels; Polyethylene glycol; Polyethylenes; Prolactin; Prolactin-Releasing Hormone - chemistry; Prolactin-Releasing Hormone - metabolism; Prolactin-releasing peptide; Research and Analysis Methods; Rodents
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0183449

Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders.