Lipidized prolactin-releasing peptide analogs: From structure to function in obesity treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00638938" target="_blank" >RIV/61388963:_____/25:00638938 - isvavai.cz</a>

Výsledek na webu

<a href="https://hdl.handle.net/11104/0369487" target="_blank" >https://hdl.handle.net/11104/0369487</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Lipidized prolactin-releasing peptide analogs: From structure to function in obesity treatment

Popis výsledku v původním jazyce

Obesity is a growing global health challenge, yet effective long-term pharmacotherapy remains limited. Prolactin-releasing peptide (PrRP) is a promising anorexigenic neuropeptide, but its clinical application is limited by stability and ability to cross the blood–brain barrier. To overcome these limitations, our laboratory developed lipidized PrRP analogs, such as palm¹¹ PrRP31, which can reduce food intake and body weight even after peripheral administration. Lipidized PrRP analogs exhibit enhanced stability and increased binding affinity toward both GPR10 (PRLHR), the canonical PrRP receptor, and neuropeptide FF receptor type 2 (NPFFR2/GPR74), which is involved in energy homeostasis and thermogenesis.nTo elucidate the mechanism of action of lipidized PrRP analogs, we employed knockout (KO) mice lacking GPR10, NPFFR2, or both receptors. GPR10 KO mice exhibited increased adiposity, hyperleptinemia, hyperinsulinemia, and impaired glucose tolerance, indicating a key role in regulating energy and glucose metabolism. NPFFR2 KO mice displayed a lean phenotype but developed marked glucose intolerance, particularly under high-fat diet conditions. Deletion of both GPR10 and NPFFR2 (double KO mice) resulted in sex-specific metabolic disturbances, including late-onset obesity, insulin resistance, and impaired glucose tolerance.nChronic treatment with palm¹¹ PrRP31 decreased food intake and body weight in wild-type mice as well as in single-receptor KO mice, but had no effect in double KO mice, confirming the necessity of both receptors for full anti-obesity effect. These findings highlight the therapeutic potential of lipidized PrRP analogs and support the dual targeting of GPR10 and NPFFR2 as a promising strategy for the treatment of obesity.n

Název v anglickém jazyce

Lipidized prolactin-releasing peptide analogs: From structure to function in obesity treatment

Popis výsledku anglicky

Obesity is a growing global health challenge, yet effective long-term pharmacotherapy remains limited. Prolactin-releasing peptide (PrRP) is a promising anorexigenic neuropeptide, but its clinical application is limited by stability and ability to cross the blood–brain barrier. To overcome these limitations, our laboratory developed lipidized PrRP analogs, such as palm¹¹ PrRP31, which can reduce food intake and body weight even after peripheral administration. Lipidized PrRP analogs exhibit enhanced stability and increased binding affinity toward both GPR10 (PRLHR), the canonical PrRP receptor, and neuropeptide FF receptor type 2 (NPFFR2/GPR74), which is involved in energy homeostasis and thermogenesis.nTo elucidate the mechanism of action of lipidized PrRP analogs, we employed knockout (KO) mice lacking GPR10, NPFFR2, or both receptors. GPR10 KO mice exhibited increased adiposity, hyperleptinemia, hyperinsulinemia, and impaired glucose tolerance, indicating a key role in regulating energy and glucose metabolism. NPFFR2 KO mice displayed a lean phenotype but developed marked glucose intolerance, particularly under high-fat diet conditions. Deletion of both GPR10 and NPFFR2 (double KO mice) resulted in sex-specific metabolic disturbances, including late-onset obesity, insulin resistance, and impaired glucose tolerance.nChronic treatment with palm¹¹ PrRP31 decreased food intake and body weight in wild-type mice as well as in single-receptor KO mice, but had no effect in double KO mice, confirming the necessity of both receptors for full anti-obesity effect. These findings highlight the therapeutic potential of lipidized PrRP analogs and support the dual targeting of GPR10 and NPFFR2 as a promising strategy for the treatment of obesity.n

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů