Energy Expenditure Homeostasis Requires ErbB4, an Obesity Risk Gene, in the Paraventricular Nucleus

Area of Science:

• Neuroscience
• Metabolic Research
• Genetics

Background:

• Obesity and major depression disorders affect a significant portion of the adult population.
• Genome-wide association studies (GWAS) have identified the receptor tyrosine kinase ErbB4 as a risk gene for both conditions.
• ErbB4 is notably enriched in the paraventricular nucleus of the hypothalamus (PVH), a key brain region for metabolic regulation.

Purpose of the Study:

• To investigate the role of ErbB4 within the PVH in regulating metabolism and energy balance.
• To explore the potential link between ErbB4, oxytocin (OXT) neurons, and the pathophysiology of depression-associated obesity.

Main Methods:

• Selective deletion of ErbB4 in the PVH of ErbB4-floxed male mice using Cre-expressing viral vectors.
• Assessment of metabolic parameters including weight gain, food intake, activity levels, and thermogenesis.
• Analysis of oxygen consumption, carbon dioxide production, and heat generation.
• Immunostaining to identify ErbB4-expressing neurons and their co-localization with oxytocin (OXT).
• Characterization of mice with ErbB4 specifically mutated in OXT+ neurons.

Main Results:

• PVH ErbB4 deletion led to increased weight gain without affecting food intake.
• Deletion resulted in reduced nighttime activity and decreased brown adipose tissue (iBAT) thermogenesis.
• ErbB4 PVH deletion independently reduced oxygen consumption, carbon dioxide production, and heat generation.
• ErbB4+ neurons in the PVH were found to be oxytocin-positive (OXT+).
• PVH ErbB4 deletion decreased serum OXT levels, and mutating ErbB4 in OXT+ neurons mimicked these metabolic phenotypes.

Conclusions:

• ErbB4 in the PVH plays a crucial role in regulating metabolism and energy expenditure.
• This regulation appears to be mediated, at least in part, through the modulation of oxytocin (OXT) expressing neurons.
• The findings reveal a novel function for ErbB4 and offer insights into the mechanisms underlying obesity associated with depression.