Ghrelin Modulates Insulin Sensitivity and Tau Phosphorylation in High Glucose-Induced Hippocampal Neurons

Abstract

Ghrelin is a 28-amino acid brain-gut peptide isolated from rat and human stomach, which is the first endogenous ligand of growth hormone secretagogue receptor 1a (GHSR-1a). 1)Ghrelin exists in the body in two forms: n-octanoyl-ghrelin (ghrelin), which contains an n-octanoyl modification at serine-3 and forms ghrelin's mark structure, and unacylated ghrelin (des-ghrelin). Acylated ghrelin is required for GHSR1a, whereas the unacylated form does not bind to GHSR1a. 2,3) GHSR-1a is widely expressed in peripheral and central tissues, including the hypothalamus, hippocampus and cortex. 4,5) Although ghrelin is predominantly produced in the X/A-like cells of the stomach in rodents, it is expressed in many other peripheral tissues and in the central nervous system 6) ; therefore, ghrelin has extensive biological action, such as stimulating food intake, regulating the secretion of gastric acid, gastric motility, 7) simulating insulin secretion, 8) modulating cell proliferation and survival, 5,9,10) immunological regulation and an anti-inflammatory effect, 11) as well as improving learning and memory, 12) the impairment of which is an Alzheimer's Disease (AD) phaenotype.AD, a devastating neurodegenerative condition, has become the fourth most fatal disease, following heart disease, cancer and stroke. AD has two pathological hallmarks: bamyloid (Ab) deposition and neurofibrillary tangles, which contain hyperphosphorylated tau protein and have a positive relation with cognitive dysfunction. In the process of tau phosphorylation, glycogen synthase kinase-3b (GSK-3b) plays an important role. Schubert demonstrated that disturbance of the insulin signaling system results in phosphorylation, whereas phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway dysfunction, which causes GSK-3b activity increase and leads to tau hyperphosphorylation. 13) Recently, some studies have indicated that AD is related to a brain insulin-resistant state that results in glucose utilization abnormalities.14) However, insulin resistance is a critical mechanism associated with type 2 diabetes and AD. Diabetic patients with insulin resistant type 2 diabetes have a 30-65% increased risk for developing AD. Type 2 diabetes is an independent risk factor for the disease. De la Monte and Wands indicated that Alzheimer's Disease could be a "type 3 diabetes." 15) Hyperglycemia, a fundamental biochemistry characteristic in diabetics, has an important role in diabetes. Hyperglycemia in type 2 diabetes is not only a secondary manifestation of insulin resistance, but could also be responsible for directly inducing insulin resistance in the target tissue. 16)However, whether a neuron is an insulin-sensitive cell is still a matter of controversy. [17][18][19] Studies have shown that hyperglycemia is a primary cause of nervous system impairment. 20) Evidence indicates that ghrelin may modulate insulin sensitivity, stimulate insulin-induced glucose uptake, 21) and modulate memory.12) Therefore, we hypothesized that ghrelin may promote hippocampal neuronal glu...

The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin

“…In fact, ghrelin administration rescued memory deficits and prevented neuronal and synaptic degeneration in the hippocampi of mice injected with Aβ [66]. Furthermore, ghrelin also decreased the levels of hyperphosphorylated Tau via the PI3K/Akt-GSK pathway, in hippocampal neurons [67]. These studies suggest that ghrelin plays a vital role not only in metabolic control, but also in regulating cognitive function and memory capacity.…”

Dietary fish oil inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by blocking nuclear factor-κB-mediated inflammatory pathways

“…AKT is known as protein kinase B (PKB), which is considered an important downstream target of PI3K. It has been reported that high glucose levels decreased activated AKT [41]. PI3K/AKT signaling pathway dysfunction caused increased activity of GSK-3β, which participated in the signal regulating of insulin path and nuclear factor-κ-gene binding (NF-κB) path [6,7].…”

Ghrelin Gene Products in Acute and Chronic Inflammation

“…This pattern was associated with a shift in the GHS-R1a/GHS-R1b ratio, suggesting an impairment of the autocrine/paracrine mechanisms (Gahete et al 2010). Conversely, ghrelin increases insulin-stimulated neuronal glucose uptake, decreases insulin resistance, and altered tau phosphorylation via the PI3-K/Akt-GSK pathway in hippocampal neuron cultures (Chen et al 2010), suggesting that it may represent a potential treatment. Indeed, in murine models of the disease, treatments with ghrelin or GHS-R1a agonists reduced the levels of amyloid-b peptide and inflammation of the microglia (Dhurandhar et al 2013;Moon et al 2011).…”