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

## TL;DR

This study shows that Connexin43 in fat cells communicates with sensory neurons through electrical connections, reducing food intake and weight gain in mice on a high-fat diet.

## Contribution

The novel finding is that electrical synapses between adipocytes and sensory neurons, mediated by Connexin43, regulate feeding behavior independently of classical adipokines.

## Key findings

- Adipocyte Cx43 overexpression reduces food intake and weight gain in mice on a high-fat diet.
- Optogenetic activation of sensory neurons in inguinal WAT mimics Cx43's effects, while sensory neuron ablation abolishes them.
- Co-culture experiments confirm adipocytes modulate sensory neuron activity via gap junctions.

## 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.

•Adipocyte Cx43 overexpression reduces food intake and weight gain in mice on a high-fat diet.•Classical adipokines (e.g., leptin, GDF15) are dispensable for this pathway.•Optogenetic activation of inguinal WAT sensory neurons mimics Cx43's effects, while sensory neuron ablation abolishes them.•Co-culture experiments confirm adipocytes directly modulate sensory neuron activity via gap junctions.•Gap junctions between adipocytes and sensory neurons may mediate appetite suppression via electrical signaling in vivo.

Adipocyte Cx43 overexpression reduces food intake and weight gain in mice on a high-fat diet.

Classical adipokines (e.g., leptin, GDF15) are dispensable for this pathway.

Optogenetic activation of inguinal WAT sensory neurons mimics Cx43's effects, while sensory neuron ablation abolishes them.

Co-culture experiments confirm adipocytes directly modulate sensory neuron activity via gap junctions.

Gap junctions between adipocytes and sensory neurons may mediate appetite suppression via electrical signaling in vivo.