Research paperIncretin hormones regulate microglia oxidative stress, survival and expression of trophic factors

- Microglia express functional GLP-1 and GIP receptors.
- Activation of incretin receptors and associated PKA pathway inhibits microglia death.
- GLP-1 and GIP upregulate microglia expression of BDNF, GDNF and NGF.
- Incretins inhibit secretion of reactive oxygen and nitrogen species by microglia.
- Incretins upregulate microglia expression of antioxidant enzymes GPx1 and SOD1.

The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are primarily known for their metabolic function in the periphery. GLP-1 and GIP are secreted by intestinal endocrine cells in response to ingested nutrients. Both GLP-1 and GIP stimulate the production and release of insulin from pancreatic β cells as well as exhibit several growth-regulating effects on peripheral tissues. GLP-1 and GIP are also present in the brain, where they provide modulatory and anti-apoptotic signals to neurons. However, very limited information is available regarding the effects of these hormones on glia, the immune and supporting cells of the brain. Therefore, we set out to resolve whether primary human microglia and astrocytes, two subtypes of glial cells, express the GLP-1 receptor (GLP-1R) and GIP receptor (GIPR), which are necessary to detect and respond to GLP-1 and GIP, respectively. We further tested whether these hormones, similar to their effects on neuronal cells, have growth-regulating, antioxidant and anti-apoptotic effects on microglia. We show for the first time expression of the GLP-1R and the GIPR by primary human microglia and astrocytes. We demonstrate that GLP-1 and GIP reduce apoptotic death of murine BV-2 microglia through the binding and activation of the GLP-1R and GIPR, respectively, with subsequent activation of the protein kinase A (PKA) pathway. Moreover, we reveal that incretins upregulate BV-2 microglia expression of brain derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in a phosphoinositide 3-kinase (PI3K)- and PKA-dependent manner. We also show that incretins reduce oxidative stress in BV-2 microglia by inhibiting the accumulation of intracellular reactive oxygen species (ROS) and release of nitric oxide (NO), as well as by increasing the expression of the antioxidant glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1). We confirm these results by demonstrating that GLP-1 and GIP also inhibit apoptosis of primary murine microglia, and upregulate expression of BDNF by primary murine microglia. These results indicate that GLP-1 and GIP affect several critical homeostatic functions of microglia, and could therefore be tested as a novel therapeutic treatment option for brain disorders that are characterized by increased oxidative stress and microglial degeneration.