title: Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca(2+) Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity.
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 Ca(2+) concentration ([Ca(2+)]i) in single NGNs. The insulin-induced [Ca(2+)]i increases were attenuated by L- and N-type Ca(2+) 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 [Ca(2+)]i increases. Systemic injection of glibenclamide rapidly released insulin and phosphorylated AKT in NGs. Furthermore, in IRS2 knockout mice, insulin action to suppress [Ca(2+)]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 Ca(2+) 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.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohno
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Enkh-Amar
authors.initials: EA
authors.lastname: Ayush
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakabayashi
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D055786:Gene Knockout Techniques; D005905:Glyburide / Q000494:pharmacology; D006963:Hyperphagia / Q000150:complications*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010179:Pancreas / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014630:Vagus Nerve / Q000187:drug effects / Q000473:pathology
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005905:Glyburide; D002118:Calcium