title: Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect.
abstract: Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-β-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ∼10-15 min after amylin treatment; the effect appeared to be dose-dependent (5-20 μg/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time- and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.
authors: Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Switzerland.
authors: Catarina Soares
authors: CS
authors: Potes
authors: Christina Neuner
authors: CN
authors: Boyle
authors: Peter John
authors: PJ
authors: Wookey
authors: Thomas
authors: T
authors: Riediger
authors: Thomas Alexander
authors: TA
authors: Lutz
mesh_terms: D000818:Animals; D000855:Anorexia / Q000503:physiopathology*; D001069:Appetite Regulation / Q000187:drug effects* / Q000502:physiology*; D031608:Area Postrema / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020546:Fourth Ventricle / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058287:Receptors, Islet Amyloid Polypeptide / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D058228:Islet Amyloid Polypeptide; D009570:Nitriles; D058287:Receptors, Islet Amyloid Polypeptide; C113580:U 0126