# Comparative Analysis of Hypothalamic Responses to Stress and Glutamine Supplementation in Diet-Induced Obese Mice: A Study of Sex Differences

## TL;DR

This study explores how stress and glutamine supplementation affect the hypothalamus in obese mice, revealing sex-specific responses.

## Contribution

The study reveals sex-specific hypothalamic responses to glutamine supplementation and stress in diet-induced obese mice.

## Key findings

- Male mice showed increased Mc4r and Bdnf mRNA levels and GFAP expression with glutamine.
- Stressed female mice exhibited upregulated Iba1 and Il6 mRNA levels and signs of microgliosis.
- Hypothalamic responses to stress and glutamine differ between male and female obese mice.

## Abstract

Hypothalamic inflammation plays a key pathophysiological mechanism linking chronic consumption of a high fat diet (HFD) to the development of obesity and associated metabolic complications. Pilot studies report that oral glutamine (Gln) supplementation might reduce waist circumference and improve metabolic and inflammatory status in obesity patients. Although Gln metabolism plays a key role in intercellular communication in the central nervous system, its potential beneficial effects remain unexplored in these contexts. Here, we aimed to evaluate how stress and glutamine supplementation can modulate the hypothalamic response to HFD in mice using a chronic-restraint stress (CRS) model, which mimics IBS symptoms. From week 12 to week 14, mice received or not Gln diluted in drinking water (2 g/kg/day) and were placed in restraint tubes (2 h/day) for the last four consecutive days of protocol. Male and female obese mice showed a difference in vulnerability to CRS-induced effects. Moreover, mice responded to Gln supplementation in a sex-dependent manner, especially in stress conditions. Hypothalamic pathways regulating energy homeostasis were more impacted in male mice, whereas factors involved in neuroinflammation were more affected in female mice. Gln supplementation led to an increase in Mc4r and Bdnf mRNA levels and GFAP expression in male mice, while upregulated Iba1 and Il6 mRNA levels as well as signs of microgliosis were observed in stressed females. In conclusion, mice with obesity showed sex-specific hypothalamic response to glutamine supplementation and stress. Further investigations should be done to decipher underlying mechanisms.

The online version contains supplementary material available at 10.1007/s10753-025-02428-9.