# Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake

## TL;DR

Alx3 deficiency affects how the body manages energy and food intake, leading to changes in body composition and hypothalamic regulation.

## Contribution

This study reveals that Alx3 is critical for regulating energy homeostasis and body composition through hypothalamic mechanisms.

## Key findings

- Alx3-deficient mice show decreased food intake but stable body weight with reduced energy expenditure.
- Alx3 deficiency is linked to increased adiposity and decreased muscle mass with signs of denervation.
- Alx3-deficient mice on high-fat diets have reduced weight gain and improved insulin sensitivity.

## Abstract

The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.

The online version contains supplementary material available at 10.1007/s00018-024-05384-z.