Glial plasticity and metabolic stability after knockdown of astrocytic Cx43 in the dorsal vagal complex

Abstract

Obesity affects well over 890 million people worldwide and causes millions of deaths each year due to metabolic complications, making it a major public health challenge. It results from a chronic imbalance between caloric intake and energy expenditure. This balance is regulated by the central nervous system, primarily by the hypothalamus and the dorsal vagal complex (DVC). The latter integrates metabolic signals from energy stores and gastrointestinal tract and coordinates autonomic responses. While historically overshadowed by a focus on neurons, the role of glial cells in regulating energy balance is now well established. Connexin 43 (Cx43) is a well-known protein expressed by astrocytes, playing a key role in glial and neuroglial communication. We previously demonstrated that pharmacological inhibition of Cx43 hemichannels (HCs) in the hypothalamus and the DVC led to anorexia in mice, accompanied by neuronal activation in both regions. To further investigate the role of astrocytic Cx43 within the DVC, where its expression is remarkably high, we developed a mouse model in which Cx43 expression is specifically reduced in DVC astrocytes using an RNA interference approach. The metabolic profile of these animals was assessed under standard feeding conditions as well as under a high-fat, high-sugar diet. Although reduced Cx43 expression led to modified glial (astrocytes and microglia) morphology and phenotype within the DVC, our analyses did not reveal significant changes in the animals metabolic phenotype. This result is surprising, given the high expression of Cx43 in the DVC and the anorexigenic effect observed with pharmacological HC inhibition. These observations raise crucial questions, about potential compensatory mechanisms involving other cell types and/or alternative neuron-glia communication pathways, as well as the DVCs ability to maintain robust control of energy homeostasis.