151. Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity
- Author
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Veronika Pražienková, Martina Holubová, Jaroslav Kuneš, Lenka Maletínská, Martin Haluzik, Martina Bugáňová, Marek Kuzma, Andrea Popelová, Blanka Železná, Miroslava Blechová, Helena Pelantová, Zdenko Pirnik, and Barbora Mikulášková more...
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Male ,0301 basic medicine ,Physiology ,Prolactin-releasing peptide ,lcsh:Medicine ,Urine ,Biochemistry ,Palmitic acid ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Glucose Metabolism ,Cricetinae ,Metabolites ,Medicine and Health Sciences ,lcsh:Science ,Receptor ,Prolactin-releasing hormone ,Prolactin-Releasing Hormone ,Multidisciplinary ,Leptin ,Fatty Acids ,Animal Models ,Lipids ,Body Fluids ,Physiological Parameters ,Experimental Organism Systems ,Adipose Tissue ,Carbohydrate Metabolism ,Anatomy ,Research Article ,medicine.medical_specialty ,Mouse Models ,CHO Cells ,Research and Analysis Methods ,Binding, Competitive ,beta-Lactamases ,03 medical and health sciences ,Cricetulus ,Model Organisms ,Palmitoylation ,Internal medicine ,medicine ,Animals ,Metabolomics ,Amino Acid Sequence ,Obesity ,Nuclear Magnetic Resonance, Biomolecular ,Triglyceride ,Nicotinamide ,lcsh:R ,Body Weight ,Biology and Life Sciences ,Diet ,Mice, Inbred C57BL ,Metabolism ,Biological Tissue ,030104 developmental biology ,Endocrinology ,chemistry ,lcsh:Q ,Peptides ,030217 neurology & neurosurgery - Abstract
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. more...
- Published
- 2017
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