Researchers at 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. Their studies in cells, animal models, and humans showed that TRPC5 acts on distinct neuronal populations in the hypothalamus, a brain region regulating multiple innate behaviors including feeding, anxiety, socialization, and maternal care. The findings, published in the journal Cell, identify TRPC5 as a diagnostic marker of obesity and postpartum depression as well as potential therapeutic strategies to treat these conditions.
“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-corresponding author Dr. Sadaf Farooqi, professor of metabolism and medicine at the University of Cambridge. “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.”
Obesity and postpartum depression are significant global health problems. According to the World Health Organization (WHO), obesity has more than doubled in adults since 1990 and quadrupled in adolescents. Postpartum depression occurs in 10 to 15% of mothers and is associated with significant maternal health problems. Globally, postpartum depression remains a major cause of death by suicide in women at a time when maternal mortality due to infections and hemorrhage has declined.
“Previous studies had shown that disrupting gene Trpc5 in the brain causes obesity due to increased food intake and reduced energy expenditure in mice,” said co-corresponding author Dr. Yong Xu, professor of pediatrics – nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center 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 each lab's individual expertise – basic genetic animal studies in the Xu lab and human genetics clinical studies in the Farooqi lab – the team was able to show that TRPC5 is an important regulator of obesity, postpartum depression, and other human behaviors.
To investigate mechanisms underlying characteristics observed in people with a defective TRPC5 gene, researchers generated a mouse model carrying a defective variant of this human gene. Male mice with this mutation gained weight on a high-fat diet and showed anxiety, increased arousal, and reduced sociability. Female mice carrying the mutation exhibited depression-like behavior after giving birth and impaired maternal-offspring interactions. Virgin female mice carrying the mutation did not show depression-like behavior.
“These studies show that characteristics seen in humans with a defective TRPC5 gene were also present in our mouse model,” Xu said.
Digging deeper into mechanisms mediating actions of this gene, researchers found it involves at least two different types of brain cells: Pomc neurons and oxytocin neurons both located within hypothalamus regions.
Pomc neurons help regulate body weight by reducing food intake; about 90% express Trpc5. Genetic disruption impaired Pomc neurons' ability to reduce appetite in mice.
High levels were also discovered within oxytocin neurons situated inside paraventricular nucleus (PVH) known for regulating energy balance alongside responses towards stress/emotion/social behaviors including mother-infant bonding.
“Removing Trpc5 from PVH oxytocin neurons caused severe overeating/obesity/postpartum depressive behavior/reduced maternal care among females,” Xu noted adding overexpressing functional genes improved conditions thus showing genetically encoded innate maternal behaviors mediated through Trpc5 affecting oxytocin neuron functionality.
“Our findings provide better understanding regarding genetic basis/neural mechanisms involved across both diseases while advancing diagnostic practices directly impacting clinical implications,” Farooqi concluded supporting screening efforts targeting specific genes ensuring accurate diagnosis possibilities while proposing potential treatment strategies directed towards identified protein roles suggesting MC4R agonist drugs treating overeating/obesity issues stemming deficient activation among Pomc neuron groups alongside exploring oxytocin receptor agonists/gene therapy restoring expressions targeting hypothalamus areas tackling postpartum depressive symptoms effectively.”
Other contributors include Yongxiang Li; Tessa M Cacciottolo; Na Yin; Yang He; Hesong Liu; Hailan Liu; Yuxue Yang; Elana Henning; Julia M Keogh; Katherine Lawler; Edson Mendes de Oliveira; Eugene J Gardner; Katherine A Kentistou Panayiotis Laouris Rebecca Bounds Ken K Ong John R B Perry Inês Barroso Longlong Tu Jonathan C Bean Meng Yu Kristine M Conde Mengjie Wang Olivia Ginnard Xing Fang Lydia Tong Junying Han Tia Darwich Kevin W Williams Yongjie Yang Chunmei Wang Shelagh Joss Helen V Firth affiliated across various institutions such as Baylor College Medicine University Cambridge Wellcome-MRC Institute Metabolic Science NIHR Cambridge Biomedical Research Center Exeter Center Excellence Diabetes Research University Exeter Medical School University Texas Southwestern Medical Center Dallas Queen Elizabeth University Hospital Glasgow Cambridge University Hospitals NHS Foundation Trust Wellcome Sanger Institute supported through Wellcome Principal Research Fellowship National Institute Health Care Research Cambridge Biomedical Research Centre Botnar Fondation Bernard Wolfe Health Neuroscience Endowment NIHR Senior Investigator Award DECIPHER project funding provided Wellcome alongside additional funds National Institutes Health grants USDA/ARS American Heart Association Fellowships American Diabetes Association Fellowship NIHR Clinical Lectureship Wellcome Transforming Genetic Medicine Initiative grant Research England Expanding Excellence England award National Institute Health Care Research Exeter Biomedical Research Center Medical Research Council Unit programs.
