TRPC5 gene identified as diagnostic marker for obesity and postpartum depression

Researchers from Baylor College of Medicine, the University of Cambridge and collaborating institutions have discovered that alterations in the human gene TRPC5 cause obesity and postpartum depression.

Taken together, their studies in cells, animal models and humans showed that TRPC5 acts on distinct neuronal populations in the hypothalamus, a brain region that regulates many innate behaviors, including feeding, anxiety, socialization and maternal care. The findings, published in the journal Cellidentify TRPC5 as a diagnostic marker for obesity and postpartum depression as well as potential therapeutic strategies to treat these conditions.

Our investigation into the role of TRPC5 The study of obesity and postpartum depression began with the discovery 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. Their mothers suffered from obesity, anxiety, and postpartum depression. We discovered that they were carriers—one of their two X chromosomes was missing the gene. TRPC5 embarrassed.”

Dr Sadaf Farooqi, co-corresponding author, Professor of Metabolism and Medicine at the University of Cambridge

Obesity and postpartum depression are major global health problems. According to the World Health Organization, obesity has more than doubled in adults since 1990 and quadrupled in adolescents. Postpartum depression affects 10–15% of mothers and is associated with significant maternal health problems. Globally, postpartum depression remains a leading cause of death by suicide among women, at a time when maternal mortality from infections and hemorrhage has declined.

The Brain Connection

“Previous studies have shown that gene disruption Trpc5 “Hematopoietic stem cell proliferation in the brain causes obesity through increased food intake and reduced energy expenditure in mice,” said co-corresponding author Dr. Yong Xu, professor of pediatrics-nutrition and associate director of basic sciences at the USDA/ARS Center for Child Nutrition Research at Baylor College of Medicine.

In the current study, the Xu lab and the Farooqi lab collaborated to investigate the role of TRPC5 in obesity and postpartum depression. By combining the individual expertise of each lab – basic animal and genetic studies in the Xu lab and human clinical and genetic studies in the Farooqi lab – the team was able to demonstrate that TRPC5 is an important regulator of obesity, postpartum depression and other human behaviors.

To study the mechanisms underlying the characteristics observed in individuals with a defect TRPC5 The researchers created a mouse model carrying a defective variant of this human gene. Male mice carrying this mutation gained weight on a high-fat diet and showed anxiety, increased arousal, and reduced sociability. Female mice carrying the mutation exhibited depressive-like behavior after delivery and impaired mother-infant interactions. Interestingly, virgin female mice carrying the mutation did not exhibit depressive-like behavior.

“These studies show that the characteristics and behaviors observed in humans with a defect TRPC5 gene were also present in our mouse model and establish that TRPC5 “regulates a spectrum of innate behaviors in mammalian species,” Xu said.

Delving deeper into the mechanisms that govern the actions of this gene, the researchers discovered that the gene's actions appear to involve at least two different types of brain cells, Pomc neurons and oxytocin neurons, both located in the hypothalamus.

Pomc neurons in the arcuate nucleus of the hypothalamus help regulate body weight by reducing food intake, and approximately 90% of these cells express Trpc5. The team found that genetic disruption of Trpc5 impaired the ability of Pomc neurons to reduce appetite in mice.

The team also found high levels of Trpc5 Expression in oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) in mice. This specific group of brain neurons is known to regulate the body's energy balance and response to stress, emotions, and social behaviors, including mother-infant bonding.

“Remove Trpc5 “The PVH oxytocin gene in mouse neurons caused severe overeating and obesity in both sexes, as well as postpartum depressive behavior and reduced maternal care in females,” Xu said. “On the other hand, overexpression of the functional gene in neurons of mice carrying a defective gene ameliorated these conditions. Together, the results show that these genetically encoded innate maternal behaviors are mediated by Trpc5 on oxytocin neurons.”

“Our findings not only provide insight into the genetic basis and neural mechanisms involved in obesity and postpartum depression, but also have direct clinical implications by advancing the diagnostic practice of these two different human diseases,” Farooqi said. “Our work supports the screening of TRPC5 “to provide a clinical diagnosis for these conditions.”

In addition, the discovery of the key role TRPC5 plays in these conditions suggests that strategies directed against this protein may potentially lead to new treatments. The authors propose that overeating and obesity in TRPC5 Oxytocin deficiency is mediated by impaired activation of Pomc neurons, this disorder can be treated with an MC4R agonist drug licensed for the treatment of genetic obesity syndromes. Oxytocin receptor agonists or gene therapy to restore TRPC5 Expression in specific areas of the hypothalamus constitutes a potential therapeutic strategy for individuals with postpartum depression.