TPH2 in the dorsal raphe nuclei regulates energy balance in a sex-dependent manner

Authors: LIU, HAILAN - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIANG, CHEN - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); WANG, LINA - Children'S Nutrition Research Center (CNRC); WANG, JULIA - Children'S Nutrition Research Center (CNRC); LIU, FENG - University Of Texas At San Antonio; HU, FANG - Central South University; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2020
Publication Date: 10/9/2020
Citation: Liu, H., Wang, C., Yu, M., Yang, Y., He, Y., Liu, H., Liang, C., Tu, L., Zhang, N., Wang, L., Wang, J., Liu, F., Hu, F., Xu, Y. 2021. TPH2 in the dorsal raphe nuclei regulates energy balance in a sex-dependent manner. Endocrinology. 162(1):1-16. https://doi.org/10.1210/endocr/bqaa183.
DOI: https://doi.org/10.1210/endocr/bqaa183

Interpretive Summary: Obesity is serious health issue to our society but the mechanisms for obesity development is still elusive. Here we discovered an enzyme, namely TPH2, in the brain that is required to prevent body weight gain in male animals but not required in female animals; we further delineated functional interaction of TPH2 and estrogen (the ovarian hormone). This work identified a potential target for obesity intervention in a specific gender.

Technical Abstract: AbstractCentral 5-hydroxytryptamine (5-HT), which is primarily synthesized by tryptophan hydroxylase 2 (TPH2) in the dorsal Raphe nuclei (DRN), plays a pivotal role in the regulation of food intake and body weight. However, the physiological functions of TPH2 on energy balance have not been consistently demonstrated. Here we systematically investigated the effects of TPH2 on energy homeostasis in adult male and female mice. We found that the DRN harbors a similar amount of TPH2+ cells in control male and female mice. Adult-onset TPH2 deletion in the DRN promotes hyperphagia and body weight gain only in male mice, but not in female mice. Ablation of TPH2 reduces hypothalamic pro-opiomelanocortin (POMC) neuronal activity robustly in males, but only to a modest degree in females. Deprivation of estrogen by ovariectomy (OVX) causes comparable food intake and weight gain in female control and DRN-specific TPH2 knockout mice. Nevertheless, disruption of TPH2 blunts the anorexigenic effects of exogenous estradiol (E2) and abolishes E2-induced activation of POMC neurons in OVX female mice, indicating that TPH2 is indispensable for E2 to activate POMC neurons and to suppress appetite. Together, our study revealed that TPH2 in the DRN contributes to energy balance regulation in a sexually dimorphic manner.