Loss of transient receptor potential channel 5 causes obesity and postpartum depression

Authors: LI, YONGXIANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); CACCIOTTOLO, TESSA - UNIVERSITY OF CAMBRIDGE; YIN, NA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HE, YANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIU, HESONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIU, HAILAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); YANG, YUXUE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HENNING, ELANA - UNIVERSITY OF CAMBRIDGE; KEOGH, JULIA - UNIVERSITY OF CAMBRIDGE; LAWLER, KATHERINE - UNIVERSITY OF CAMBRIDGE; MENDES DE OLIVEIRA, EDSON - UNIVERSITY OF CAMBRIDGE; GARDNER, EUGENE - CAMBRIDGE INSTITUTE OF MEDICAL RESEARCH; KENTISTOU, KATHERINE - CAMBRIDGE INSTITUTE OF MEDICAL RESEARCH; LAOURIS, PANAYIOTIS - UNIVERSITY OF CAMBRIDGE; BOUNDS, REBECCA - UNIVERSITY OF CAMBRIDGE; ONG, KEN - CAMBRIDGE INSTITUTE OF MEDICAL RESEARCH; PERRY, JOHN - UNIVERSITY OF CAMBRIDGE; BARROSO, INES - UNIVERSITY OF EXETER; TU, LONGLONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); BEAN, JONATHAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); YU, MENG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); CONDE, KRISTINE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); WANG, MENGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); GINNARD, OLIVIA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); FANG, XING - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); TONG, LYDIA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HAN, JUNYING - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); DARWICH, TIA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); WILLIAMS, KEVIN - UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER; YANG, YONGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); WANG, CHUNMEI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); JOSS, SHELAGH - QUEENS UNIVERSITY - UNITED KINGDOM; FIRTH, HELEN - CAMBRIDGE UNIVERSITY; XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); FAROOQI, I - CAMBRIDGE INSTITUTE OF MEDICAL RESEARCH

Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/31/2024
Publication Date: 7/2/2024
Citation: Li, Y., Cacciottolo, T.M., Yin, N., He, Y., Liu, H., Liu, H., Yang, Y., Henning, E., Keogh, J.M., Lawler, K., Mendes De Oliveira, E., Gardner, E.J., Kentistou, K.A., Laouris, P., Bounds, R., Ong, K.K., Perry, J.R., Barroso, I., Tu, L., Bean, J.C., Yu, M., Conde, K.M., Wang, M., Ginnard, O., Fang, X., Tong, L., Han, J., Darwich, T., Williams, K.W., Yang, Y., Wang, C., Joss, S., Firth, H.V., Xu, Y., Farooqi, I. 2024. Loss of transient receptor potential channel 5 causes obesity and postpartum depression. Cell. https://doi.org/10.1016/j.cell.2024.06.001.
DOI: https://doi.org/10.1016/j.cell.2024.06.001

Interpretive Summary: Hypothalamic neural circuits control natural behaviors like looking for food, responding to threats, socializing, and caring for offspring. We found small deletions on chromosome Xq23 that affect the brain-expressed TRP channel 5 (TRPC5). These channels detect sensory signals and convert them into electrical signals that the brain can understand. Men with TRPC5 deletions showed behaviors like food seeking, obesity, anxiety, and autism, which were also seen in male mice with a similar TRPC5 mutation. Women with TRPC5 deletions had severe postpartum depression. Female mice with the TRPC5 mutation showed lack of pleasure and depression-like behavior, along with poor care for their young. Deleting Trpc5 from oxytocin neurons in the hypothalamus led to obesity in both sexes and postpartum depression in females. Overexpressing Trpc5 in these neurons reversed these issues in the mice. Our study shows that TRPC5 is crucial for important human behaviors related to survival, such as food seeking and maternal care.

Technical Abstract: Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.