Regulation of Food Intake by Connexin43 via Adipocyte-Sensory Neuron Electrical Synapses

Authors

Xi Chen
Xing Fang
Hong Zhou
Jieyi Meng
Yang He
Leon G Straub
Andrew Lemoff
Clair Crewe
Shangang Zhao
Yong Xu
Yi Zhu

Language

English

Publication Date

9-5-2025

Journal

Molecular Metabolism

DOI

10.1016/j.molmet.2025.102247

PMID

40915562

Abstract

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusions: Gap junction-mediated electrical communication between adipocytes and sensory neurons may regulate feeding.

Keywords

Adipocytes, Connexin 43, Electrical synapses, Food intake, Gap junction, Sensory neurons

Published Open-Access

yes

Recommended Citation

Chen, Xi; Fang, Xing; Zhou, Hong; et al., "Regulation of Food Intake by Connexin43 via Adipocyte-Sensory Neuron Electrical Synapses" (2025). Duncan NRI Faculty and Staff Publications. 153.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/153