Regulation of food intake by Connexin43 via adipocyte-sensory neuron electrical synapses

Authors: CHEN, XI - Children'S Nutrition Research Center (CNRC); FANG, XING - Children'S Nutrition Research Center (CNRC); ZHOU, HONG - Children'S Nutrition Research Center (CNRC); MENG, JIEYI - Children'S Nutrition Research Center (CNRC); HE, YANG - Baylor College Of Medicine; STRAUB, LEON - University Of Hamburg; LEMOFF, ANDREW - University Of Texas Southwestern Medical Center; CREWE, CLAIR - Washington University School Of Medicine; ZHAO, SHANGANG - University Of Texas Health Science Center; XU, YONG - Children'S Nutrition Research Center (CNRC); ZHU, YI - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2025
Publication Date: 9/5/2025
Citation: Chen, X., Fang, X., Zhou, H., Meng, J., He, Y., Straub, L.G., Lemoff, A., Crewe, C., Zhao, S., Xu, Y., Zhu, Y. 2025. Regulation of food intake by Connexin43 via adipocyte-sensory neuron electrical synapses. Molecular Metabolism. 101. Article 102247. https://doi.org/10.1016/j.molmet.2025.102247.
DOI: https://doi.org/10.1016/j.molmet.2025.102247

Interpretive Summary: This study found that increasing Connexin43 in fat cells helped mice eat less, gain less fat, and use more fat for energy when they were fed a high-fat diet. The reduced eating was not caused by GDF15, but depended on sensory nerves in fat tissue. The results suggest that fat cells may communicate with nearby nerves through gap junctions to help control feeding behavior.

Technical Abstract: Connexin43 (Cx43), encoded by Gja1, forms gap junctions between adjacent cells. In adipose tissue, it is upregulated during adipose beiging while downregulated by high-fat-diet (HFD) feeding. Adipocyte-specific Gja1 overexpression enhances adipose tissue beiging in response to mild cold stress of room temperature. Moreover, those mice display a surprising decrease in food intake, but the mechanism remains unclear. This study investigates how adipocyte Cx43 influences feeding behavior. Mice with adipose tissue-specific Gja1 overexpression (Adipoq-Cx43) were fed with HFD. Food intake, weight gain, substrate utilization, and serum lipolysis were assessed. RNA-seq, proteomics, and cytokine measurements were employed to identify candidate signals. Sensory neurons were manipulated via subcutaneous capsaicin injection or iWAT-targeted optogenetics. Co-culture of adipocytes and sensory neurons in vitro was used to test gap junction communication between these two types of cells. Adipoq-Cx43 mice showed reduced food intake, fat mass, and weight gain on HFD, and shifted substrate utilization toward fatty acids. Although GDF15 was elevated, its neutralization did not reverse the reduced food intake. Instead, systemic ablation of sensory neurons using capsaicin abolished the suppressed food intake. Ooptogenetic activation of sensory neurons in iWAT acutely reduced food intake and improved glucose tolerance after two weeks. In the co-culture of adipocytes and in vitro differentiated sensory neurons, optogenetic stimulation of adipocytes enhanced firing of the adjacent sensory neurons via gap junctions, an effect blocked by the gap junction inhibitor carbenoxolone. Gap junction–mediated electrical communication between adipocytes and sensory neurons may regulate feeding.