Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake

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.

NF-κB and AP-1 are required for the lipopolysaccharide-induced expression of MCP-1, CXCL1, and Cx43 in cultured rat dorsal spinal cord astrocytes

“…In addition, TAK-242 at 100 nM was used in order to confirm the role of TLR4 in LPS-induced inflammatory response in cultured astrocytes ( Du et al, 2017 ). It is reported that CBX, Gap26, and Gap19 at 100 μM were frequently used in order to establish the involvement of Cx43 in neuroactive substance release from astrocytes ( Takaki et al, 2012 ; Guillebaud et al, 2020 ). PDTC at 1 μM and SR11302 at 10 μM were frequently used in order to establish the involvement of NF-κBp65 and AP-1 signaling in cellular responses ( Zhao et al, 2015 ; Liddell et al, 2016 ).…”

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

“…Cx43 was often found in the vicinity of synaptic elements. Moreover, the icv injection of TAT-GAP19, a specific blocker of Cx43 HCs, decreases food intake and induces neuronal activation in the hypothalamus and DVC [129]. Altogether, these results suggest a possible release, within the DVC and through glial Cx43 HCs, of molecules with modulatory action on energy balance.…”

“…Alternatively, connexins not engaged in GJ form hemichannels (HCs), which are permeable by small molecules, such as glucose, ATP, D-serine, and glutamate [128]. Guillebaud et al [129] reported that Cx43 is strongly expressed by DVC glial cells. Cx43 was often found in the vicinity of synaptic elements.…”

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

“…Astrocytes also exhibit appropriate levels of Panx1, and both Cx43 and Panx1 form functional astroglial hemichannels and pannexons, respectively, on in vitro and ex vivo preparations [118,[140][141][142][143]. Cellular signaling and gliotransmitter release via the opening of astrocytic hemichannels and pannexons underpin relevant biological processes at the nervous system, including neuronal oscillations [144], astroglial migration [145], food intake [146], synaptic transmission, and plasticity [132,[147][148][149], as well as memory consolidation and behavior [150,151] (Figure 3). Despite the above, the uncontrolled activation of these channels in astrocytes associate with the pathogenesis and progression of homeostatic imbalance in various neuropathological diseases [111,112,[114][115][116][117][118][119][120][121][122].…”

“…Last but not least, exacerbated hemichannel/pannexon activity may trigger the release of high amounts of molecules potentially toxic for neighboring cells, such as glutamate, in the case of the CNS [111,112] (Figure 3). receptor signaling, contributes to diverse biological brain processes (bottom left panel), including synaptic plasticity [132,[147][148][149], neuronal oscillations [144], food intake [146], astroglial migration [145], fear memory consolidation [151], and behavior [150]. The top right panel shows a reactive astrocyte (in gray) in a pathophysiological scenario.…”