Summary: A new study has identified the TRPC5 gene as a cause of obesity, behavioral disorders, and postnatal depression. The researchers found that missing or altered TRPC5 genes disrupt oxytocin neurons, which are essential for regulating appetite and emotions. This discovery offers potential new treatments, such as using oxytocin to relieve symptoms. The findings highlight the biological basis of certain behaviors and conditions.
Highlights:
- The TRPC5 gene affects appetite, anxiety and social behavior.
- Disruption of TRPC5 affects oxytocin neurons, leading to weight gain and depression.
- Oxytocin treatment shows promise in reducing these symptoms.
Source: University of Cambridge
Scientists have identified a gene that, when missing or altered, can cause obesity, behavioral problems and, in mothers, postnatal depression.
The discovery, reported today in Cellcould have broader implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may relieve symptoms.
Obesity and postnatal depression are major global health problems. Postnatal depression affects more than one in ten women in the first year after giving birth and is associated with an increased risk of suicide, which accounts for one in five maternal deaths in high-income countries. At the same time, obesity has more than doubled among adults since 1990 and quadrupled among adolescents, according to the World Health Organization.
Investigating two boys from different families suffering from severe obesity, anxiety, autism and behavioural problems triggered by sounds or smells, a team led by scientists from the University of Cambridge, UK, and Baylor College of Medicine, Houston, US, found that the boys lacked a single gene, known as TRPC5which is found on the X chromosome.
Further research revealed that both boys had inherited the gene deletion from their mother, who was missing the gene on one of their X chromosomes. The mothers were also obese, but had also suffered from postnatal depression.
To test whether it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically modifying mice with a defective version of the gene (Trpc5 In mice).
Male mice carrying the defective gene exhibited the same problems as boys, including weight gain, anxiety, aversion to social interactions and aggressive behavior.
Female mice exhibited the same behaviors, but when they became mothers, they also displayed depressive behavior and impaired maternal care. Interestingly, male mice and female mice that were not mothers but carried the mutation did not exhibit depressive behavior.
Dr. Yong Xu, associate director for basic sciences at the USDA/ARS Center for Child Nutrition Research at Baylor College of Medicine, said, “What we saw in these mice was quite remarkable. They exhibited behaviors very similar to those seen in people without TRPC5 “The gene responsible for these behaviors is a gene that, in mothers, manifests itself in signs of depression and difficulties in caring for their baby. This shows us that this gene is at the origin of these behaviors.”
TRPC5 is part of a family of genes involved in detecting sensory signals, such as heat, taste, and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.
When the researchers looked at this region of the brain in more detail, they found that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often dubbed the “love hormone” because of its release in response to displays of affection, emotion and bonding.
Deleting the gene for these oxytocin neurons led to otherwise healthy mice exhibiting similar signs of anxiety, overeating, and reduced sociability and, in the case of the mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.
In addition to acting on oxytocin neurons, the team showed that TRPC5 The POMC gene also acts on so-called POMC neurons, which have long been known to play an important role in weight regulation. Children in whom the POMC gene does not function properly often have an insatiable appetite and gain weight from an early age.
Professor Sadaf Farooqi of the Institute of Metabolic Sciences at the University of Cambridge said: “There is a reason why people who are lacking TRPC5 develop all of these conditions. We have long known that the hypothalamus plays a key role in regulating “instinctive behaviors” – which allow humans and animals to survive – such as foraging, social interaction, the flight-or-fight response, and caring for infants.
“Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a vital role in regulating our instincts.
While the deletions of TRPC5 Because the G1 and G2 genes are rare, an analysis of DNA samples from around 500,000 individuals in the UK Biobank found that 369 people – around three-quarters of them women – carried variants of the gene and had a higher than average body mass index.
The researchers say their findings suggest that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers suffering from postnatal depression.
Professor Farooqi said: “Although some genetic diseases such as TRPC5 “Oxytocin deficiencies are very rare, but they teach us important lessons about how the body works. In this case, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite decades of research. And importantly, it could indicate that oxytocin could be a possible treatment for some mothers with this condition.”
There is already evidence in animals that the oxytocin system is involved in both depression and maternal care, and small trials have been conducted on the use of oxytocin as a treatment. The team say their work provides direct evidence of the role of oxytocin, which will be crucial to support larger multicentre trials.
Professor Farooqi added: “This study reminds us that many behaviours we assume are entirely within our control have a strong biological basis, whether it’s our eating behaviour, our anxiety or our postnatal depression. We need to be more understanding and sympathetic to people who suffer from these conditions.”
Funding: This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), the NIHR Cambridge Biomedical Research Centre, the Fondation Botnar and the Bernard Wolfe Health Neuroscience Endowment.
About this news on genetics and neuroscience research
Author: Craig Brierley
Source: University of Cambridge
Contact: Craig Brierley – University of Cambridge
Picture: Image credited to Neuroscience News
Original research: Free access.
“Loss of transient receptor potential channel 5 causes obesity and postpartum depression” by Yong Xu et al. Cell
Abstract
Loss of transient receptor potential channel 5 causes obesity and postpartum depression
Strong points
- In humans, the suppression of TRPC5 causes obesity, anxiety, autism and postpartum depression
- Male and female mice hosting a human TRPC5 the mutation recapitulates these phenotypes
- The effects are mediated by TRPC5 acting on hypothalamic Pomc neurons and oxytocin
- TRPC5 expressed in the brain regulates instinctive behaviors essential for survival
Summary
Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, fight/flight response, socialization, and maternal care.
We identified microdeletions on chromosome Xq23 that disrupt the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals that can be interpreted by the brain.
Male TRPC5 Deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in male human loss-of-function knockin mice TRPC5 mutation.
Women wearing TRPC5 Female knock-in mice exhibited severe postpartum depression. As mothers, they exhibited anhedonia and depressive-like behavior with impaired care for their offspring.
Deletion of Trpc5 oxytocin neurons in the hypothalamic paraventricular nucleus induced obesity in both sexes and postpartum depressive behavior in women, while Trpc5 Overexpression in oxytocin neurons in knock-in mice reversed these phenotypes.
We demonstrate that TRPC5 plays a critical role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.