Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake

International audienceThe metabolic syndrome, which comprises obesity and diabetes, is a major public healthproblem and the awareness of energy homeostasis control remains an important worldwide issue.The energy balance is finely regulated by the central nervous system (CNS), notably through neuronalnetworks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional,humoral and nervous information from the periphery. The glial cells’ contribution to these processesemerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronalnetwork activity. In the present study, we sought to determine the possible involvement of glial Cx43HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamusand DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 withsynaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamicCx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally,we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamicslices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide thatspecifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injectionstrongly decreased food intake, without further alteration of glycaemia, energy expenditures orlocomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intakeregulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated withglial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesit