期刊
PLOS ONE
卷 12, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0183449
关键词
-
资金
- Grant Agency of the Czech Republic [15-08679S, 13-14105S]
- Operational Program Prague Competitiveness [CZ.2.16/3.1.00/24023]
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-erminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, gamma-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.
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