Cell sub-journal: Astral glial cells maintain a steady state of mitochondria and promote learning and memory.

Astrocyte is a kind of cell widely existing in the brain. At first, it was thought that this kind of cell only played a supporting role. With the in-depth study of this type of cell, its role gradually surfaced.recent studies have shown that astrocytes play a key role in the regulation of glucose and energy metabolism. Astrocytes not only regulate systemic glucose and energy homeostasis by responding to leptin and insulin signals, but also regulate brain metabolism by controlling glucose transport to adapt to behavioral changes.the picture shows that glucagon like peptide-1 (GLP-1) is a brain gut peptide secreted by endocrine cells in the ileum.in islets, GLP-1 promotes Glucose dependent insulin secretion and inhibits glucagon release, which makes GLP-1 one of the main targets for the treatment of type 2 diabetes mellitus.with regard to the market competition of GLP-1 receptor agonists, some drugs have entered the clinical application, including Eli Lilly's GLP-1 receptor agonists exenatide and dulaglycopeptide, hausen's GLP-1 receptor agonist losenatide, Novo Nordisk's long-acting GLP-1 receptor agonist somaluptide, etc.interestingly, astrocytes also express glucagon like peptide (GLP) - 1 receptor (GLP-1R).then whether the endogenous GLP-1R signal of astrocytes is involved in the regulation of energy metabolism and glucose homeostasis.on June 2, 2020, Professor Jens C. bruning of Max Planck Institute of metabolism, Germany, published an article in the top magazine cell metabolism, which revealed that the endogenous GLP-1R signal of astrocytes maintains the homeostasis of mitochondria and relies on FGF21 to regulate glucose metabolism (1).in which brain regions do astrocytes express GLP-1R? In situ hybridization showed that GLP-1R was expressed in astrocytes in arcuate nucleus (ARH), paraventricular nucleus (PVH), nucleus of solitary tract (NTS) and hippocampus.in vitro experiments showed that GLP-1R expression was promoted in astrocytes at low and high glucose concentrations.after GLP-1R knockout mice were knocked out by virus tool and loxP tool, astrocytes in hypothalamus of GLP-1R knockout mice were cultured in primary culture to construct GLP-1R knockout astrocytes (hereinafter referred to as GLP-1R knockout cells in vitro).previous studies have shown that mitochondria play a key role in the adaptive feedback mechanism of hypothalamic neurons in regulating energy and glucose homeostasis (2).in addition, under the condition of low and high glucose concentration, the glycolysis ability of GLP-1R knockout cells in vitro was enhanced and glucose intake was promoted.in addition, the production of mitochondrial ATP in astrocytes was decreased, and the maximal mitochondrial respiration was weakened.morphological analysis showed that the length of mitochondria of astrocytes was elongated, and the adaptive changes of acute glucose administration were made by fusion and fission.the researchers constructed GLP-1R specific knockout mice (hereinafter referred to as specific GLP-1R knockout mice), and found that in the glucose tolerance test, the ability of GLP-1R knockout mice to "clear" the glucose in peripheral tissues was improved, and the insulin sensitivity was enhanced. The specific performance was that the glucose uptake of white adipose tissue was significantly increased, and the grape in brown adipose tissue was increased Glucose uptake showed an increasing trend, but it did not exist in skeletal muscle.in addition, PET imaging showed that glucose transport increased in olfactory bulb, hippocampus, hypothalamus and other brain regions. this increase in glucose intake is not caused by differences in weight, body composition, etc. these results further indicate that GLP-1R specific knockout of astrocytes promotes glucose metabolism. FGF21 (fibroblast growth factor-21) has always been considered as an endocrine factor regulating lipid metabolism, glucose metabolism and insulin sensitivity. studies have shown that continuous intraventricular injection of FGF21 can enhance glucose tolerance in rats (3). the expression of FGF21 in hypothalamus of GLP-1R knockout mice was increased. Injection of FGF21 neutralizing antibody into the brain region could significantly reverse the enhancement of glucose metabolism induced by specific GLP-1R knockout. in addition, the specific knockout of FGF21 on astrocytes has a similar effect to that of injecting FGF21 neutralizing antibody. these results suggest that FGF21 on astrocytes is involved in the enhancement of glucose metabolism induced by GLP-1R knockout. studies have shown that decreased brain glucose uptake is associated with cognitive impairment (4). The spatial learning ability of the water maze knockout mice was also enhanced when the astrocytes were knocked out. this indicates that the enhancement of spatial learning ability of GLP-1R knockout mice depends on FGF21 signal. In general, GLP-1 inhibits glucose uptake and promotes the utilization of fatty acids in astrocytes, and reveals the role of GLP-1R signal transduction in maintaining mitochondrial integrity: the lack of GLP-1R signal in astrocytes induces adaptive response, improves systemic glucose metabolism, and promotes memory Formation. References: 1. Timper et al., GLP-1 receptor signaling in astrocytes regulates fatty acid oxidation, mitochondrial integrity, and function, cell metabolism (2020), T., and Langer, T. (2016). Microbiological dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105 – 1173. Sarruf, D.A., Thaler, J.P., Morton, G.J, German, J., Fischer, J.D., Ogimoto, K.,and Schwartz, M.W. (2010). Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 59,1817–18244.Jais, A., Solas, M., Backes, H., Chaurasia, B., Kleinridders, A., Theurich, S.,Mauer, J., Steculorum, S.M., Hampel, B., Goldau, J., et al. (2016). Myeloidcell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell 165, 882–895