Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes

Abstract

Astrocytes are the most abundant cell type in the brain and crucial to ensure the metabolic supply of neurons and their synapse formation. Overnutrition as present in patients suffering from obesity causes astrogliosis in the hypothalamus. Other diseases accompanied by malnutrition appear to have an impact on the brain and astrocyte function. In the eating disorder anorexia nervosa (AN), patients suffer from undernutrition and develop volume reductions of the cerebral cortex, associated with reduced astrocyte proliferation and cell count. Although an effect on astrocytes and their function has already been shown for overnutrition, their role in long-term undernutrition remains unclear. The present study used primary rat cerebral cortex astrocytes to investigate their response to chronic glucose starvation. Cells were grown with a medium containing a reduced glucose concentration (2 mM) for 15 days. Long-term glucose starvation increased the expression of a subset of pro-inflammatory genes and shifted the primary astrocyte population to the pro-inflammatory A1-like phenotype. Moreover, genes encoding for proteins involved in the unfolded protein response were elevated. Our findings demonstrate that astrocytes under chronic glucose starvation respond with an inflammatory reaction. With respect to the multiple functions of astrocytes, an association between elevated inflammatory responses due to chronic starvation and alterations found in the brain of patients suffering from undernutrition seems possible.

The Role of Glial Cells in Regulating Feeding Behavior: Potential Relevance to Anorexia Nervosa

“…Cell culture studies additionally gave interesting insights into glia cell pathology. An in vitro semi-starvation model in primary rat astrocytes has been established in our group by Kogel et al [ 124 ]. The cells were treated with a low glucose concentration (2 mM) in the culture medium for 15 days to mimic chronic semi-starvation.…”

Different Methods for Evaluating Microglial Activation Using Anti-Ionized Calcium-Binding Adaptor Protein-1 Immunohistochemistry in the Cuprizone Model

“…The ramification index was calculated as illustrated in Figure 1 D–F). According to Kogel et al, the ramification index is defined as the ratio of the cell area (A c ) and the projection area (A p ) [ 37 ]. To measure A c , the anti-IBA1-positive area of one individual cell was outlined using the polygon tool in ImageJ.…”

Glial cells in anorexia

“…Thus, DIA induces a pro-inflammatory environment that involves microglia and possibly also astrocytes. Indeed, astrocytes react to starvation with a pro-inflammatory response that correlates with the expression of pro-inflammatory genes ( Kogel et al, 2021 ). Furthermore, DIA reduced the expression of glial fibrillary acidic protein (GFAP, a classical astrocytic marker) and the number of GFAP + cells in the corpus callosum and hippocampus ( Reyes-Haro et al, 2015 , 2016 ).…”