Role of astrocytic connexins in hypothalamic glucose sensing mechanism : involvement on the nervous control of metabolism – ConnexSensing

Hypothalamus plays a critical role in both the monitoring and the regulation of energy needs. Energy stores are monitored by the hypothalamus using metabolic and neural signals from the periphery. These signals trigger neuroendocrine, autonomic and behavioral responses, maintaining energy homeostasis. Hypothalamic neurons responding to glucose levels have been identified, but the process allowing the transfer of blood glucose to these hypothalamic sensitive neurons remains unclear. Glucose sensing implies the glucose inhibited (GI) or glucose excited (GE) neurons. GE neurons respond to increased glucose concentration and are mainly found in the arcuate nucleus. The mechanisms underlying glucose responsiveness of these neurons share similarities with pancreatic beta-cells. One of these shared mechanisms is the redox signaling through mitochondrial reactive oxygen species (mROS) production when glucose rises, especially through the conversion of the superoxide anions production into H2O2. Moreover, evidence shows that in the hypothalamus glucose responsiveness implies two populations of cells, i.e. the GE neurons themselves and upstream, the astrocytes which appear absolutely required. Indeed, studies have highlighted that the entire effect of glucose requires its conversion to lactate, which is performed by astrocytes. However, whether important studies have highlighted this metabolic coupling mechanism between the two populations, any of them have focus on upstream actors that allow the final supply of lactate to GE neurons. This early step in providing the information of the circulating glycemic level to GE neurons might be of prime importance to ensure a right transduction of the metabolic status of the body to the hypothalamus. Astrocytes are a physical link between vasculature and neurons through their perivascular endfeet. Moreover, perivascular astrocytes have a high level of connexin (Cx) expression. Cxs are the gap junction channel-forming proteins and allow direct intercellular communication as these channels are permeable to small signaling molecules. In astrocytes they constitute the morphological support for astroglial networks. These networks ensure an intercellular pathway between gliovascular interface and the neuronal energy demand. Recently, using fluorescent glucose derivatives it was reported that astroglial metabolic networks are regulated by neuronal activity in the hippocampus. In addition, in absence of external glucose, the trafficking of lactate through astroglial networks was sufficient to maintained synaptic activity. These findings highlights that gap-junctions mediated metabolic networks contribute to the delivery of energetic substrates to neurons. In the case of GE neurons, the connectivity through connexins of the astrocytic network, allowing the intercellular trafficking of glucose and its metabolites, might take a crucial importance. Another interesting feature of this astrocytic network is its sensitivity to superoxide anions through H2O2 derivative. The requirement of increased mROS for adequate responses of GE neurons to glucose rises and the H2O2-induced increased permeability of gap-junctions mediated metabolic network suggest that a redox regulated interplay between de two cell populations might exist.
Implication of astrocytes through the release of lactate in brain glucose sensing has been demonstrated, but the study of upstream trafficking of glucose and its metabolites has never been undertaken. Moreover, the understanding of glucose fluxes through astroglial networks in metabolic diseases such as obesity or diabetes, where defects in brain glucose sensing are well characterized, might be of prime importance in the etiology of disturbed autonomic controls and/or food intake. Consequently, the objective of this project is to explore the causal links between metabolic trafficking through astroglial networks and hypothalamic glucose sensing mechanism at molecular, cellular and physiological levels.