GLP-1 secretion by microglial cells and decreased CNS expression in obesity

Abstract

BackgroundType 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain.MethodsHere we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA.ResultsWe show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon.ConclusionThe findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

“…Despite the differential levels of TNFα mRNA in the BV-2 microglia treated with palmitate for 4 and 24 h, co-culturing with mHypoE-46 hypothalamic neurons resulted in a similar trend towards a decrease in TNFα mRNA in the neurons. The decrease in the mRNA of TNFα, a potent pro-inflammatory marker, in the mHypoE-46 neurons may indicate an anti-inflammatory effect of the BV-2 microglia by alternative activation, as previously suggested [20, 21]. The neuroprotective potential of microglia has also been shown in co- culture models with dopaminergic neurons [63], but the influence of microglia on palmitate-mediated neuroinflammation remains controversial.…”

“…Previous studies have suggested that microglia are the essential players in the increased expression of inflammatory cytokines that leads to neurotoxicity in a high-fat environment [19]. On the contrary, other studies have shown that palmitate may induce an alternative, anti-inflammatory response in microglia, resulting in neuroprotection [20, 21]. It is likely that both are possible given the temporal responses necessary for resolution of an acute inflammatory response versus the chronic neuroinflammation seen with long-term exposure to high fat [22].…”

The nature, significance, and glucagon‐like peptide‐1 analog treatment of brain insulin resistance in Alzheimer's disease

“…GLP-1 is one of two incretin peptides that are so named because their secretion by the intestines in response to food increases glucose-stimulated pancreatic insulin release [106]. Like insulin, it is produced in the brain, specifically by autonomic brainstem neurons [107] and by cerebrocortical and hippocampal microglia [108]. Also, like insulin, it has many functions outside the pancreas, including neuroprotection [109,110], promotion of neurogenesis [110,111], and potentiation of insulin signaling [112,113].…”

Cardiorenal Metabolic Syndrome and Diabetic Cognopathy

“…Of great interest was the finding of the proglucagon gene and the secretion of GLP-1 in a cyclic adenosine monophosphate-dependent manner in MGCs. Importantly, MGCs may be a central brain source for GLP-1 secretion, and in insulin-resistant conditions the expression and secretion of GLP-1 and mRNA expression of proglucagon are decreased, which heightens the importance of MGC activation in excess nutrition, obesity, IR, and T2DM and its relation to early neurodegeneration [63]. Accordingly, dipeptidyl peptidase 4 inhibitor therapy may have beneficial effects to attenuate the multiple toxicities that promote DC in diabetic patients.…”

“…Incretin hormones such as glucagon-like peptide 1 (GLP-1) have anti-inflammatory properties, are neuroprotective, and reduce appetite in addition to stimulating insulin secretion, and are being investigated as therapies for AD [63]. GLP-1 mimetics such as extendin-4 used clinically for the treatment of T2DM are currently being used in a clinical trial by the National Institute of Aging.…”