Abstract
Some of insulin’s functions, including glucose/lipid metabolism, satiety and neuroprotection, involve the alteration of brain activities. Insulin could signal to the brain via penetrating through the blood-brain barrier and acting on the vagal afferents, while the latter remains unproved. This study aimed to clarify whether insulin directly regulates the nodose ganglion neurons (NGNs) of vagal afferents in mice. NGs expressed insulin receptor (IR) and insulin receptor substrate-2 (IRS2) mRNA, and some of NGNs were immunoreactive to IR. In patch-clamp and fura-2 microfluorometric studies, insulin (10−12∼10−6 M) depolarized and increased cytosolic Ca2+ concentration ([Ca2+]i) in single NGNs. The insulin-induced [Ca2+]i increases were attenuated by L- and N-type Ca2+ channel blockers, by phosphatidylinositol 3 kinase (PI3K) inhibitor, and in NGNs from IRS2 knockout mice. Half of the insulin-responsive NGNs contained cocaine- and amphetamine-regulated transcript. Neuronal fibers expressing IRs were distributed in/around pancreatic islets. The NGNs innervating the pancreas, identified by injecting retrograde tracer into the pancreas, responded to insulin with much greater incidence than unlabeled NGNs. Insulin concentrations measured in pancreatic vein was 64-fold higher than that in circulation. Elevation of insulin to 10−7 M recruited a remarkably greater population of NGNs to [Ca2+]i increases. Systemic injection of glibenclamide rapidly released insulin and phosphorylated AKT in NGs. Furthermore, in IRS2 knockout mice, insulin action to suppress [Ca2+]i in orexigenic ghrelin-responsive neurons in hypothalamic arcuate nucleus was intact while insulin action on NGN was markedly attenuated, suggesting a possible link between impaired insulin sensing by NGNs and hyperphagic obese phenotype in IRS2 knockout mice These data demonstrate that insulin directly activates NGNs via IR-IRS2-PI3K-AKT-cascade and depolarization-gated Ca2+ influx. Pancreas-innervating NGNs may effectively sense dynamic changes of insulin released in response to nutritional states. These interactions could serve to convey the changes in pancreatic and systemic insulin to the brain.
Highlights
The vagal afferents, as well as the blood-brain barrier (BBB), serve as the anatomical and functional routes for signaling from the periphery to the brain
We examined whether insulin receptor substrate-2 (IRS2), phosphatidylinositol 3 kinase (PI3K) and/or mitogenactivated protein kinase (MAPK), key molecules for insulin signaling, are involved in the insulin-induced [Ca2+]i increases in nodose ganglion (NG) neurons
insulin receptor (IR) and IRS2 were expressed in NG neurons, and the insulin-induced increases in [Ca2+]i were suppressed by blockade of IRS2, PI3K, L-type and N-type Ca2+ channels
Summary
The vagal afferents, as well as the blood-brain barrier (BBB), serve as the anatomical and functional routes for signaling from the periphery to the brain. It has been reported that 0.046% of peripheral insulin penetrates BBB [10], that insulin receptor (IR) is expressed in the brain [11], and that neuron-specific deletion of IRs in the brain alters fuel metabolism, reproduction, and hepatic glucose production [11] as well as inducing diet-sensitive obesity and female-selective hyperphagia [12]. Evidences shown in these reports support that insulin exerts the central action at least partly via its direct interaction with IRs on the neurons in the brain. It has been reported that the local branches of vagal afferents that innervate particular organs/tissues play an important role in sensing/ conveying the local information to the brain [13]
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