Could “Love Hormones” Treat Obesity and Postnatal Depression?

Scientists from the University of Cambridge have identified a gene that can cause obesity, behavioral issues and postnatal depression when missing or impaired. The study, published in Cell, points to oxytocin as a potential treatment.

Obesity and postnatal depression are major global health concerns

Around 1 in 10 pregnant women experience a mental health condition, which can sometimes become so severe that it leads to suicide. These mental health issues can negatively impact the child's growth and development, affecting their physical, emotional and cognitive well-being.

Obesity affects one in eight people and can increase the risk of many health conditions, such as type 2 diabetes and cardiovascular disease. Since 1990, rates of obesity have more than doubled worldwide, and the global obesity crisis is becoming a major public health concern that necessitates urgent action to implement effective prevention and treatment strategies.

Previous studies have identified the role of hypothalamic neural circuits in regulating human behaviors such as food-seeking and maternal care. These circuits sense changes in the internal and external environment and select the most adaptive behavior response, leading to variability in hard-wired innate behaviors. Understanding how these internal mechanisms impact human behavior is vital for developing prevention and treatment techniques for obesity and postnatal health.

TRPC5 impacts human and animal behavior

A team of researchers investigated two boys, from separate families, who suffered from severe obesity, anxiety, autism and behavioral issues triggered by sounds or smells. Both patients were missing a single gene, TRPC5, which is found on the X chromosome. TRPC5 is in a family of genes that plays a role in detecting sensory signals such as heat, taste and touch. The gene acts on a pathway found in the hypothalamus region of the brain, which also impacts appetite.

Upon further investigation, they found both boys had inherited the gene deletion from their mothers who also had the gene missing on one of their X chromosomes. Strikingly, the mothers also suffered from obesity and had both experienced postnatal depression.

The researchers used animal models to test the role of TRPC5 in the development of the issues identified in the boys and their mothers. They identified similar phenotypes in mice genetically engineered to harbor a defective version of the gene. They also exhibited increased weight gain, anxiety, issues with social interactions and aggression. Both male and female mice displayed the same behavior – however, when the female mice became mothers, they displayed depressive behavior and impaired maternal care. Female mice that did not become mothers and male mice did not show any depression-like symptoms, despite carrying the same mutation.

“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,” said Dr. Yong Xu, associate director for basic sciences at the Children’s Nutrition Research Center at Baylor College of Medicine.

TRPC5 acts on oxytocin neurons

The researchers took a closer look at how TRPC5 acts on the hypothalamus and found it impacts oxytocin neurons, the nerve cells responsible for producing the hormone oxytocin. Oxytocin, known as the "love hormone”, is often released in response to displays of affection and bonding.

Deleting the TRPC5 gene from oxytocin neurons in healthy mice resulted in a similar display of behavior as seen in the TRPC5-impaired mice. Restoring the gene caused a reduction in body weight and in symptoms of anxiety and postnatal depression.

TRPC5 was also found to act on POMC neurons, a group of neurons that play a role in regulating weight. Previous research has identified a defective POMC gene in children results in an insatiable appetite and increased weight gain from an early age.

Restoring oxytocin in TRPC5-impaired individuals

Although TRPC5 deletions are rare, an analysis of DNA samples from individuals in the UK Biobank discovered that those that did had a higher-than-average body mass index.

“There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviors’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts,” said Dr. Sadaf Farooqi, a professor from the Institute of Metabolic Science at the University of Cambridge.

The researchers hope their study could lead to treatment options in the future for people who are missing or have a defective TRPC5 gene.

“While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition,” said Farooqi.

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

Reference: Li Y, Cacciottolo TM, Yin N, et al. Loss of transient receptor potential channel 5 causes obesity and postpartum depression. Cell. 2024. doi: 10.1016/j.cell.2024.06.001

This article is a rework of a press release issued by the University of Cambridge. Material has been edited for length and content.