Scientists have discovered a gene whose absence or impairment can lead to obesity, behavioral issues, and postnatal depression in mothers. Published today in Cell, this finding could have broader implications for treating postnatal depression. A study in mice indicates that oxytocin may help alleviate symptoms.

Obesity and postnatal depression are significant global health issues. Postnatal depression affects more than one in ten women within a year of childbirth and is linked to an increased suicide risk, accounting for up to one in five maternal deaths in high-income countries. Meanwhile, obesity rates have more than doubled in adults and quadrupled in adolescents since 1990, according to the World Health Organization.

Researchers from the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, studied two boys from different families with severe obesity, anxiety, autism, and behavioral problems triggered by sounds or smells. They discovered that both boys lacked a gene called TRPC5 on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. These mothers also had obesity and experienced postnatal depression.

To confirm the TRPC5 gene’s role in these issues, researchers created genetically-engineered mice with a defective version of the gene (Trpc5 in mice). Male mice with the defective gene displayed the same problems as the boys, including weight gain, anxiety, social avoidance, and aggressive behavior. Female mice exhibited similar behaviors, and as mothers, they also showed depressive behavior and impaired maternal care. Notably, male mice and non-mother female mice with the mutation did not show depression-like behavior.

Dr. Yong Xu from Baylor College of Medicine stated, “What we saw in those mice was quite remarkable. They displayed very similar behaviors to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and difficulty caring for their babies. This shows us that this gene is causing these behaviors.”

TRPC5 belongs to a family of genes involved in detecting sensory signals like heat, taste, and touch. This gene acts on a pathway in the hypothalamus, a brain region known to control appetite. The researchers found that TRPC5 acts on oxytocin neurons, which produce the hormone oxytocin, known as the ‘love hormone’ due to its role in bonding and affection.

Deleting the gene from oxytocin neurons led to otherwise healthy mice showing signs of anxiety, overeating, and impaired sociability, and postnatal depression in mothers. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

Additionally, TRPC5 acts on POMC neurons, which regulate weight. Children with non-functioning POMC genes often have an insatiable appetite and gain weight early.

Professor Sadaf Farooqi from the University of Cambridge said, “There’s a reason why people lacking TRPC5 develop all of these conditions. The hypothalamus regulates ‘instinctive behaviors,’ such as seeking food, social interaction, the fight or flight response, and caring for infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While TRPC5 gene deletions are rare, an analysis of DNA samples from around 500,000 individuals in the UK Biobank identified 369 people, mostly women, with gene variants linked to a higher-than-average body mass index.

The researchers suggest that restoring oxytocin could help treat individuals with defective TRPC5 genes and potentially mothers experiencing postnatal depression.

Professor Farooqi said, “Some genetic conditions, like TRPC5 deficiency, are very rare but teach us important lessons about how the body works. We have made a breakthrough in understanding postnatal depression, a serious health issue about which little is known despite decades of research. Importantly, it may point to oxytocin as a potential treatment for some mothers with this condition.”

Evidence already exists that the oxytocin system is involved in depression and maternal care in animals, and small trials have investigated oxytocin as a treatment. This research provides direct proof of oxytocin’s role, supporting the need for larger, multi-center trials.

Professor Farooqi concluded, “This research reminds us that many behaviors we assume are entirely under our control have a strong biological basis, whether it’s our eating behavior, anxiety, or postnatal depression. We need to be more understanding and sympathetic towards people who suffer from these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Foundation, and Bernard Wolfe Health Neuroscience Endowment.

 

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