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

Obesity affects more than a third adult population in the United States; the prevalence is even higher in patients with major depression disorders. GWAS studies identify the receptor tyrosine kinase ErbB4 as a risk gene for obesity and for major depression disorders. We found that ErbB4 was enriched in the paraventricular nucleus of the hypothalamus (PVH). To investigate its role in metabolism, we deleted ErbB4 by injecting a Cre-expressing virus into the PVH of ErbB4-floxed male mice and found that PVH ErbB4 deletion increased weight gain without altering food intake. ErbB4 PVH deletion also reduced nighttime activity and decreased intrascapular brown adipose tissue (iBAT) thermogenesis. Analysis of covariance (ANCOVA) revealed that ErbB4 PVH deletion reduced O(2) consumption, CO(2) production and heat generation in a manner independent of body weight. Immunostaining experiments show that ErbB4+ neurons in the PVH were positive for oxytocin (OXT); ErbB4 PVH deletion reduces serum levels of OXT. We characterized mice where ErbB4 was specifically mutated in OXT+ neurons and found reduction in energy expenditure, phenotypes similar to PVH ErbB4 deletion. Taken together, our data indicate that ErbB4 in the PVH regulates metabolism likely through regulation of OXT expressing neurons, reveal a novel function of ErbB4 and provide insight into pathophysiological mechanisms of depression-associated obesity.