Abstract
The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem 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 neuronal networks, 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 processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 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 hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.
Highlights
IntroductionThe energy balance is finely regulated by the central nervous system (CNS), notably through neuronal
The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the comprehension of energy homeostasis control remains an important worldwide issue.The energy balance is finely regulated by the central nervous system (CNS), notably through neuronalCells 2020, 9, 2387; doi:10.3390/cells9112387 www.mdpi.com/journal/cellsCells 2020, 9, 2387 networks, located in the hypothalamus and the dorsal vagal complex (DVC) including the nucleus tractus solitarius (NTS), which integrate nutritional, humoral and nervous information from the periphery and in turn adjust energy expenditure and food intake
Recent studies showed that glial cells in both the hypothalamus [1,2,3] and brainstem [4,5,6] interact with neurons and in turn finely tune energy homeostasis
Summary
The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal. Cells 2020, 9, 2387 networks, located in the hypothalamus and the DVC including the nucleus tractus solitarius (NTS), which integrate nutritional, humoral and nervous information from the periphery and in turn adjust energy expenditure and food intake. Decoding the precise mechanisms regulating energy balance remains a challenge necessary to efficiently treat metabolic disorders. Recent studies showed that glial cells in both the hypothalamus [1,2,3] and brainstem [4,5,6] interact with neurons and in turn finely tune energy homeostasis. The mechanisms of neuron-glia interactions in the context of food intake control remain to be deciphered. A typical feature of glial cells is their high expression level of Cx43, a protein able to form gap junction (GJ) channels, and connexin 43 hemichannels (Cx43 HCs), in allowing the release of neuroactive substances
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