TRPC5 Mutations Linked to Obesity, Postpartum Depression

Research led by Baylor College of Medicine and the University of Cambridge has discovered mutations in the gene TRPC5, located on the X chromosome, that can cause obesity and postpartum depression.

This gene is expressed in the hypothalamus in the brain and is thought to impact a number of different processes around the body ranging from neuronal control to expression of fear and anxiety.

“Our investigation into the role of TRPC5 in obesity and postpartum depression began with the finding that the X chromosomes of two unrelated boys with intense food-seeking behavior, severe obesity, and other altered behaviors were missing a small piece that included this gene,” said co-lead investigator Sadaf Farooqi, professor of metabolism and medicine at the University of Cambridge, in a press statement.

“Their mothers had obesity, anxiety and postpartum depression. We found that they were carriers—one of their two X chromosomes was missing the TRPC5 gene.”

After this initial finding, the current study investigated how widespread mutations in TRPC5 were in people with obesity and the general population, as well as looking at how this gene is expressed in a mouse model.

As reported in the journal Cell, the researchers looked for TRPC5 variants in 984 people with childhood-onset obesity in the Genetics of Obesity Study and also in the general population in the approximately 450,000 people with exome sequencing data in the UK Biobank.

They discovered seven rare TRPC5 coding variants in the Genetics of Obesity Study group that appeared to impact function of the gene. In the UK Biobank group, 88 men and 281 women were carriers of TRPC5 variants, and these individuals had significantly higher body mass index than non-carriers.

In a mouse model, high expression levels of the mouse version of TRPC5 gene were seen in the hypothalamus region of the brain similar to humans. Loss of function of this gene in the mouse model led to obesity in male and female mice and postpartum-depression like behavior in female mice. Notably, the behavior was not seen in female mice who had not given birth.

“Removing the TRPC5 gene from the paraventricular nucleus of the hypothalamus oxytocin neurons in mice caused severe overeating and obesity in both sexes and postpartum depressive behavior and reduced maternal care in females,” said co-lead author Yong Xu, professor of pediatrics nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at the Baylor College of Medicine.

“On the other hand, overexpressing the functional gene in the neurons of mice carrying a defective gene improved these conditions. Together, the results show that these genetically encoded innate maternal behaviors are mediated by TRPC5 on oxytocin neurons.”

More work is needed to widen and validate these findings, but the authors believe their research could help people impacted by these mutations. The investigators have identified what they believe causes obesity and postpartum depression related to mutations in the TRPC5 gene, namely, malfunctioning Pomc neurons in the hypothalamus. Treatment with an MC4R agonist, oxytocin receptor agonists or gene therapy could help treat people with these mutations in the future.