PEGylated neuromedin U-8 shows long-lasting anorectic activity and anti-obesity effect in mice by peripheral administration

Peptides. 2017 Aug:94:99-105. doi: 10.1016/j.peptides.2017.04.001. Epub 2017 Apr 8.

Abstract

Neuromedin U (NMU) is a neuropeptide found in the brain and gastrointestinal tract. The NMU system has been shown to regulate energy homeostasis by both a central and a peripheral mechanism. Peripheral administration of human NMU-25 was recently shown to inhibit food intake in mice. We examined the possibility that other NMU-related peptides exert an anorectic activity by intraperitoneal (i.p.) administration. We found that rat NMU-23 and its structurally-related peptide rat neuromedin S (NMS) significantly reduced food intake in lean mice, whereas NMU-8, an active fragment of the octapeptide sequence conserved in porcine, human and mouse NMU, had no effect. When rat NMU-23, NMU-8, and rat NMS were covalently conjugated to polyethylene glycol (PEG) (PEGylation) at the N-terminus of these peptides, PEGylated NMU-8 showed the most long-lasting and robust anorectic activity. The exploration of the linker between NMU-8 and PEG using hetero-bifunctional chemical cross-linkers led to an identification of PEGylated NMU-8 analogs with higher affinity for NMU receptors and with more potent anorectic activity in lean mice. The PEGylated NMU-8 showed potent and robust anorectic activity and anti-obesity effect in diet-induced obesity (DIO) mice by once-daily subcutaneous (s.c.) administration. These results suggest that PEGylated NMU-8 has the therapeutic potential for treatment of obesity.

Keywords: Neuromedin S; Neuromedin U; PEGylation.

MeSH terms

  • Animals
  • Appetite Depressants / administration & dosage
  • Appetite Depressants / pharmacology*
  • Eating / drug effects
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuropeptides / administration & dosage
  • Neuropeptides / chemistry
  • Neuropeptides / pharmacology*
  • Obesity / drug therapy*
  • Polyethylene Glycols / chemistry
  • Rats

Substances

  • Appetite Depressants
  • Neuropeptides
  • neuromedin S
  • neuromedin U
  • Polyethylene Glycols
  • neuromedin U 8