3 years ago

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

Miroslava Blechová, Barbora Mikulášková, Zdenko Pirník, Martina Bugáňová, Jaroslav Kuneš, Martina Holubová, Marek Kuzma, Martin Haluzík, Blanka Železná, Andrea Popelová, Veronika Pražienková, Lenka Maletínská, Helena Pelantová

by Veronika Pražienková, Martina Holubová, Helena Pelantová, Martina Bugáňová, Zdenko Pirník, Barbora Mikulášková, Andrea Popelová, Miroslava Blechová, Martin Haluzík, Blanka Železná, Marek Kuzma, Jaroslav Kuneš, Lenka Maletínská

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.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.pone.0183449

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