# Modulating food intake by nasal application of peptides targeting melanocortin 4 receptor and ghrelin receptor systems

## TL;DR

This study shows that nasal delivery of specific peptides can influence food intake in mice by targeting brain receptors involved in appetite regulation.

## Contribution

The study demonstrates the effectiveness of intranasal peptide delivery to modulate food intake via melanocortin 4 and ghrelin receptors in mice.

## Key findings

- Setmelanotide variants reduced daily food intake in mice.
- GhrR agonists increased daily food intake in mice.
- Peptides reached the hypothalamus after intranasal application.

## Abstract

The regulation of appetite by pharmaceuticals has gained significant interest for the treatment of obesity and cachexia. The melanocortin 4 receptor (MC4R) and the ghrelin receptor (GhrR) are known to play a crucial role in the regulation of energy homeostasis. Thus, peptide ligands, which modulate these receptors, have become attractive therapeutic lead structures. A key challenge is the efficient delivery of such peptides to the targeted receptors, which are expressed in the hypothalamus. Therefore, direct nose-to-brain delivery is a compelling strategy. Here, we report on food intake that is modulated by using intranasal applied peptides. We synthesized fluorescently labelled variants of the MC4R agonist setmelanotide, the GhrR agonist ghrelin (Ghr) and the GhrR inverse agonist KbFwLL-NH2 [β-(3-benzothienyl)-D-alanine (b)] and assessed their receptor activity. Further, we measured the permeability and stability of these peptides on Calu-3 cells as a model system for the nasal mucosa. Next, the uptake of peptides after intranasal application was analysed in vivo by quantification of fluorescent signals in the olfactory bulb, cortex and hypothalamus. In addition, we monitored the effects of the two most promising peptides on food intake in vivo. Although no significant changes in body weight were observed, we detected differences in the daily change in food intake: this parameter was reduced for mice treated with setmelanotide variants and increased for mice treated with GhrR agonists compared to a control group. Taken together, our findings clearly underline the high potential of intranasal peptide administration for modulating food intake.

Özbay et al. demonstrated that intranasal administration of peptides targeting melanocortin 4 and ghrelin receptors can modulate food intake in mice. Their study shows that selected peptides successfully reach the hypothalamus, supporting the potential of nasal peptide delivery for treating obesity and cachexia.

Graphical Abstract