SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis

Authors: YU, MENG - Children'S Nutrition Research Center (CNRC); BEAN, JONATHAN - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); CAI, XING - Children'S Nutrition Research Center (CNRC); YU, KAIFAN - Children'S Nutrition Research Center (CNRC); PEI, ZHOU - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); LI, YONGXIANG - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); SCARCELLI, NIKOLAS - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - University Of Illinois; HE, YANLIN - Louisiana State University; XU, YONG - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC)

Submitted to: Cell & Bioscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/27/2022
Publication Date: 10/9/2022
Citation: Yu, M., Bean, J., Liu, H., He, Y., Yang, Y., Cai, X., Yu, K., Pei, Z., Liu, H., Tu, L., Conde, K., Wang, M., Li, Y., Yin, N., Zhang, N., Han, J., Scarcelli, N., Xu, P., He, Y., Xu, Y., Wang, C. 2022. SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis. Cell & Bioscience. 12. Article 170. https://doi.org/10.1186/s13578-022-00907-2.
DOI: https://doi.org/10.1186/s13578-022-00907-2

Interpretive Summary: This study investigated the role of small conductance calcium-activated potassium (SK) current in pro-opiomelanocortin (POMC) neurons in regulating body weight and glucose balance in mice, and how it differs between males and females. The study found that POMC neurons express SK3, a subunit of the SK channel, and deleting SK3 from mature POMC neurons affected energy and glucose homeostasis differently in male and female mice. Male mice with SK3 deficiency had decreased food intake and physical activity, while female mice showed impaired glucose balance. Interestingly, no differences in body weight were observed between the mutant and control groups. The study also found that male POMC neurons co-expressing estrogen receptor a had higher SK current but lower SK3 positive neuron population compared to females. These findings suggest a sexually dimorphic role of SK3 in POMC neurons in regulating energy and glucose homeostasis independent of body weight control.

Technical Abstract: Pro-opiomelanocortin (POMC) neurons play a sexually dimorphic role in body weight and glucose balance. However, the mechanisms for the sex differences in POMC neuron functions are not fully understood. We detected small conductance calcium-activated potassium (SK) current in POMC neurons. Secondary analysis of published single-cell RNA-Seq data showed that POMC neurons abundantly express SK3, one SK channel subunit. To test whether SK3 in POMC neurons regulates POMC neuron functions on energy and glucose homeostasis, we used a Cre-loxP strategy to delete SK3 specifically from mature POMC neurons. POMC-specific deletion of SK3 did not affect body weight in either male or female mice. Interestingly, male mutant mice showed not only decreased food intake but also decreased physical activity, resulting in unchanged body weight. Further, POMC-specific SK3 deficiency impaired glucose balance specifically in female mice but not in male mice. Finally, no sex differences were detected in the expression of SK3 and SK current in total POMC neurons. However, we found higher SK current but lower SK3 positive neuron population in male POMC neurons co-expressing estrogen receptor a (ERa) compared to that in females. These results revealed a sexually dimorphic role of SK3 in POMC neurons in both energy and glucose homeostasis independent of body weight control, which was associated with the sex difference of SK current in a subpopulation of POMC + ERa + neurons.