# Semaglutide Exacerbates Stunting in Growth-Impaired Juvenile Male Mice via Reduced Energy Metabolism

## TL;DR

Semaglutide worsens growth problems in stunted juvenile male mice by reducing energy metabolism, even without affecting food intake or weight.

## Contribution

The study reveals semaglutide's role in exacerbating growth impairment via metabolic changes in stunted juveniles.

## Key findings

- Semaglutide lowers blood glucose without affecting food intake or weight in normally growing juveniles.
- In growth-stunted mice, semaglutide worsens growth impairment through reduced food intake and catabolic activity.
- GLP-1 signaling interacts with energy metabolism and growth during juvenile development.

## Abstract

Animals rely on linear growth to attain their full adult size. The regulators of this multifactorial process, including environmental and endocrine cues, are still incompletely understood. Notably, GLP-1, glucagon-like peptide 1 (GLP-1) has emerged as a potential player in this process. Here, we employ semaglutide, a pharmaceutical GLP-1R agonist as a tool to mechanistically dissect the interplay between GLP-1 receptor activation, energy metabolism, and linear growth during the juvenile period, independent of its clinical applications. Using a juvenile mouse model, we show that chronic semaglutide treatment lowers blood glucose without affecting food intake or weight gain in juveniles with a normal growth pattern. However, in growth-stunted juveniles, semaglutide treatment exacerbates linear growth impairment through at least 2 concomitant mechanisms: a moderate reduction in food intake, and a decreased catabolic activity incompatible with tissue growth. These data suggest a complex interplay between GLP-1 signaling, energy metabolism, and growth during juvenile development. Overall, these findings highlight the value of semaglutide as a mechanistic tool for understanding how GLP-1 receptor activation modulates growth and metabolism in juveniles, emphasizing the importance of developmental context for interpreting its effects.