Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Abstract

Potes CS, Boyle CN, Wookey PJ, Riediger T, Lutz TA. Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect. Am J Physiol Regul Integr Comp Physiol 302: R340 -R351, 2012. First published November 30, 2011 doi:10.1152/ajpregu.00380.2011.-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-␤-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 ϳ10 -15 min after amylin treatment; the effect appeared to be dosedependent (5-20 g/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.ERK; MAPK; area postrema; amylin receptor; U0126 THE HOMEOSTATIC SYSTEM CONTROLLING food intake and body weight relies to a large extent on peripheral satiation signals.One of these signals is amylin, a peptide cosecreted with insulin by pancreatic ␤-cells in response to nutrient ingestion (12, 41). At near-physiological plasma concentrations, amylin effectively decreases food intake in rats, and is considered a physiological satiation signal (4, 27). The amylin analog pramlintide causes weight loss in obese humans that is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies (5, 57).Pharmacological and lesioning studies implicate the area postrema (AP) as the primary site of amylin's anorectic action (29,30,35), and an excitatory action of amylin on AP neurons has been confirmed by electrophysiological studies (49). Immunohistochemical studies using the immediate early gene product c-Fos as a marker of neuronal activation showed that peripheral amylin activates the AP, and subsequently the nucleus of the solitary tract (NTS),...

Amylin: Pharmacology, Physiology, and Clinical Potential

“…For phosphorylation of ERK1/2 and increases in intracellular Ca 2+ , amylin can certainly trigger these events but interestingly, the potency of amylin only increases slightly in the presence of RAMP when measuring these pathways compared with cAMP Qi et al, 2013). Nevertheless, the time course of rapid ERK1/2 phosphorylation by amylin in cells transfected with calcitonin and amylin receptors is consistent with its time course for activation in AP neurons (see section VI.B) and osteoclasts (Dacquin et al, 2004;Morfis et al, 2008;Potes et al, 2012;Qi et al, 2013). Activation of ERK1/2 is clearly a pathway that amylin can use, but more work is needed to determine the precise circumstances under which this occurs and the mechanism involved.…”

“…The AP also seems to be necessary for amylin's action to inhibit gastric emptying (Young et al, 1995;Gedulin et al, 1997;Wickbom et al, 2008;Mack et al, 2010;Young, 2005b). Electrophysiological and immunohistochemical studies supported a direct influence of amylin on the AP (Riediger et al, , 2002Potes et al, 2010bPotes et al, , 2012. As discussed in section III of this article, the receptor components (calcitonin receptor, RAMPs) necessary for amylin function appear to be expressed in the AP.…”

“…Markers that may also be functionally linked to amylin are the formation of the second messenger cGMP or the phosphorylation of ERK1/2 (Potes et al, 2012). Local AP injection of a membrane permeable analog of cGMP decreased eating similar to amylin by a meal size effect (Mollet et al, 2004).…”

Amylin Receptor Signaling in the Ventral Tegmental Area is Physiologically Relevant for the Control of Food Intake

“…For example, amylin excites AP neurons , likely through a glutamatergic mechanism (Fukuda et al, 2013). Within the AP, the extracellular signalregulated kinase 1/2 pathway is important for the anorectic effects of amylin (Potes et al, 2012), and norepinephrine neurons partially mediate these effects as well (Potes et al, 2010). Other central neurotransmitter systems including histamine are implicated in the intake-suppressive effects of peripherally administered amylin (Lutz et al, 1996;Mollet et al, 2001Mollet et al, , 2003Seth et al, 2012).…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…Amylin leads to a phosphorylation of ERK, and this effect may be involved in the rapid effects of amylin on eating because at least under certain conditions, inhibition of ERK phosphorylation prevented the effect of amylin. 61 Part of the amylin-activated AP neurons seem to express dopamine-β-hydroxylase, which characterizes noradrenergic neurons. In fact,~50% of amylin activation seems to occur in neurons expressing dopamine-β-hydroxylase 39,62 while the phenotype of the remainder of amylin-activated neurons is unclear; at least part of them may be second-order neurons, which therefore do not necessarily express amylin receptors and the amylin signaling transduction machinery themselves.…”