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

Abstract

Eating behavior is controlled by hypothalamic circuits in which agouti-related peptide-expressing neurons when activated in the arcuate nucleus, promote food intake while pro-opiomelanocortin-producing neurons promote satiety. The respective neurotransmitters signal to other parts of the hypothalamus such as the paraventricular nucleus as well as several extra-hypothalamic brain regions to orchestrate eating behavior. This complex process of food intake may be influenced by glia cells, in particular astrocytes and microglia. Recent studies showed that GFAP⁺ astrocyte cell density is reduced in the central nervous system of an experimental anorexia nervosa model. Anorexia nervosa is an eating disorder that causes, among the well-known somatic symptoms, brain volume loss which was associated with neuropsychological deficits while the underlying pathophysiology is unknown. In this review article, we summarize the findings of glia cells in anorexia nervosa animal models and try to deduce which role glia cells might play in the pathophysiology of eating disorders, including anorexia nervosa. A better understanding of glia cell function in the regulation of food intake and eating behavior might lead to the identification of new drug targets.

Keywords: anorexia nervosa; astrocyte; glia cells; hypothalamus.

Figure 1

A schematic illustration of the control of food intake in the arcuate nucleus (ARC) of the hypothalamus. In this nucleus, two subpopulations of neurons, the orexigenic NPY/AgRP neurons, and anorexigenic POMC neurons, regulate the process of food intake. These neurons communicate with other hypothalamus nuclei such as the paraventricular nucleus (PVN), the lateral hypothalamic area (LHA), and the parabrachial nucleus (PBN). As metabolic hormone leptin can signal to the ARC by inhibiting NPY/AgRP neurons leading to reduced food intake. Furthermore, leptin activates POMC neurons resulting in decreased food intake. In contrast, ghrelin stimulates NPY/AgRP neurons and signals to orexigenic pathways. GABA, gamma-aminobutyric acid; MSH, melanocyte-stimulating hormone.

Figure 2

A schematic illustration of food intake regulation in the ARC when AgRP neurons are removed. As a result, starvation or anorexia occurs, while a direct application of bretazenil (a GABA_A receptor partial agonist) into the parabrachial nucleus (PBN) protects from starvation in adult mice. Modified from Wu et al., 2009. PVN, paraventricular nucleus.

Figure 3

The role of astrocytes in glutamate uptake. Glutamate is released into the synaptic cleft. Glutamate transporter 1 (GLT-1) and L-glutamate/L-aspartate transporter (GLAST) transfer glutamate into astrocytic cells. Glutamine synthetase (GS) converts glutamate into glutamine. Glutamine is released from astrocytes via specific transporters and then taken up into neurons. In the neuron, glutamine is converted to glutamate.

Figure 4

Effects of chronic starvation on GFAP⁺ cell densities in the cerebral cortex (A) and the corpus callosum (C) in activity-based anorexia (ABA) rat model. The arrows mark GFAP⁺ astrocytes. GFAP⁺ cell densities and mean mRNA expression of Gfap were reduced after starvation in the ABA group compared to the control group. After refeeding Gfap mRNA expression was reversed to control levels in both brain regions (B,D). *** p ≤ 0.001, two-sided student’s t-test. Modified from Frintrop et al., 2019.

Figure 5

The interaction between neurons, microglia, and astrocytes in the control of food intake. Under healthy conditions, the regulation of food intake resembles a homeostatic interplay of glia cells and neurons (A). Astrocytes act for example as glucose sensors and influence plasticity through their contact with synapses. A hypothetic model demonstrates the starvation-induced effects in the hypothalamus in anorexia animal models, e.g., a decrease in astrocyte cell number and function and an increase in microglia cell number as a result of neuroinflammation (B). ARC, arcuate nucleus.