Open AccessImpact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity
Author(s) -
Veronika Pražienková,
Martina Holubová,
Helena Pelantová,
Martina Bugáňová,
Zdeno Pirník,
Barbora Mikulášková,
Andrea Popelová,
Miroslava Blechová,
Martin Haluzı́k,
Blanka Železná,
Marek Kuzma,
Jaroslav Kuneš,
Lenka Maletı́nská
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0183449
Subject(s) - chemistry , palmitic acid , leptin , endocrinology , medicine , receptor , fatty acid , triglyceride , pharmacology , biochemistry , obesity , cholesterol
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 Lys 11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys 11 , 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 Lys 11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys 11 (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.