Glucose Manipulation Leads to Hypothalamic Dysfunction via Hypoxic Mechanisms

The hypothalamus plays a central role in maintaining key homeostatic mechanisms in the body including regulation of blood glucose levels (Jenkins, 1972; Williams et al., 2001). Dramatic reductions in the latter (hypoglycemia) trigger the activation of various immune cells and proinflammatory cytokines in the hypothalamus. These responses are also associated with other stressful conditions such as low levels of oxygen (hypoxia). In the brain, the main non-neuronal cell typesthat are involved in regulating physiologicalresponses are the microglia and astrocytes (Luarte et al., 2017; Sugama et al., 2019). Previous studies have shown that acute hypoglycemia can lead to activation of hypothalamic microglia resulting in an increased secretion of proinflammatory cytokines in the hypothalamus (Winkler et al., 2019). In addition, it was found that the host’s defense mechanism has evolved to induce the activation of hypoxia inducible factor-1 (HIF-1) in response to hypoxia. This factor undergoes stabilization to form the HIF-1α subunit which further leads to its heterodimerization with the HIF-1β subunit, resulting in the activation of the HIF-1 pathway and its target genes such as EPO, VEGF, and Glut-1 (Cimmino et al., 2019; Dengler et al., 2014; Xiao et al., 2013). Interestingly, in astrocytes, inhibiting the degradation of HIF-1α upregulates the expression of the proinflammatory cytokine IL-1β but whether the same happens in microglial cells remains unclear (Zhang et al., 2006). Given the critical role of HIF-1 in regulating the cellular responses to stressful conditions such as hypoglycemia and hypoxia, it is of great interest to investigate the factors that influence the involvement of HIF-1/ HIF-1α in hypothalamic non-neuronal microglia and astrocytes. 2 Additionally, investigating the cross talk between these cells under the abovementioned stressful conditions will help in providing valuable insights into the immune microenvironment and the corresponding signaling pathways that are crucial for maintaining neuronal homeostasis. Astrocytic lactate signaling within the hypothalamus seems to be crucial for glucose sensing and central regulation of glucose homeostasis (Yoon & Diano, 2021). HIF-1 target genes such as glucose and lactate transporters and lactate dehydrogenase A are thought to be important for this regulatory mechanism. HIF-1 expression is up regulated by pro-inflammatory cytokines via the NFkB pathway and pro-inflammatory nitric oxide has been shown to stabilize HIF-1α protein in astrocytes (Brix et al., 2012; Jung et al., 2003). In turn, HIF-1 activation may induce IL1β expression which further contributes to HIF activation. Thus, it can be proposed that HIF-1α is activated in hypothalamic glia during glycemia induced inflammation. Our preliminary data showed that microglia were sensitive to glucose manipulation and significant activation (indicated by expression of BDNF) was observed in response to increased glucose concentrations. Interestingly, HIF-1α was downregulated in response to hypoxia, it seems that the involvement of HIF-1α is more complex than previously thought (Figure 1, page 4) Based on the discussed points, we hypothesize that the results of the present project will highlight potential therapeutic targets for hypoglycemic-hypoxic stress that is associated with various metabolic disorders including diabetes mellitus.