Amylin potently activates AP neurons possibly via formation of the excitatory second messenger cGMP

Abstract

Amylin is secreted with insulin from the pancreas during and after food intake. One of the most potent actions of amylin in vivo is its anorectic effect, which is directly mediated by the area postrema (AP), a circumventricular organ lacking a functional blood-brain barrier. As we recently demonstrated, amylin also stimulates water intake most likely via its excitatory action on subfornical organ (SFO) neurons. Neurons investigated under equal conditions in an in vitro slice preparation of the rat AP were 15-fold more sensitive to amylin than SFO neurons. Amylin (10(-11)-10(-8) M) excited 48% of 94 AP neurons tested; the remaining cells were insensitive. The average threshold concentration of the excitatory response was 10(-10) M and, thus, close to physiological plasma concentrations. Coapplication of the amylin receptor antagonist AC-187 reduced amylin's excitatory effect. Amylin-mediated activation of AP neurons and antagonistic action of AC-187 were confirmed in vivo by c-fos studies. Peripherally applied amylin stimulated cGMP formation in AP and SFO neurons, as shown in immunohistochemical studies. This response was independent of nitric oxide (NO) formation in the AP, while coapplication of the NO synthase inhibitors N-monomethyl-L-arginine (100 mg/kg) and nitro-L-arginine methyl ester (50 mg/kg) blocked cGMP formation in the SFO. In contrast to the SFO, where NO-dependent cGMP formation seems to represent a general inhibitory transduction pathway, cGMP acts as an excitatory second messenger in the AP, since the membrane-permeable analog 8-bromo-cGMP stimulated 65% of all neurons tested (n = 17), including seven of nine amylin-sensitive neurons (77%). The results indicate that the anorectic effect of circulating amylin is based on its excitatory action on AP neurons, with cGMP acting as a second messenger.

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

“…The presence of fully functional amylin receptors in the AP is consistent with the co-expression of cyclic GMP, which is one of the second messengers of amylin receptor activation, 25,60 in CTR carrying AP neurons. 34 Another second messenger system activated by amylin is the ERK/MAPK system.…”

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

“…Previous study has shown the anorexigenic effects of amylin to be mediated through the AP. [14][15][16] At doses producing equal magnitudes of food intake suppression, davalintide and amylin failed to decrease food intake in AP-lesioned rats, suggesting that, similar to amylin ( 17,18 and current study), the AP is also a critical brain nucleus mediating the anorexigenic action of davalintide. Sustained exposure of davalintide decreased body weight over 8 weeks and was associated with decreased fat mass and lean sparing, similar to previous reported effects with amylin.…”

“…Amylin's action is mediated by activation of amylin-binding sites in the area postrema (AP) as lesioning this site abolishes its ability to reduce food intake. [14][15][16] c-Fos expression is observed in the AP after systemic amylin treatment, as well as in additional upstream pathways, including the nucleus tractus solitarii (NTS), lateral parabrachial nucleus (lPBN) and central amygdala. 17 Amylin has also been shown to reverse fastinginduced c-fos activation in the lateral hypothalamic area.…”

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

“…Amylin activation of calcitonin receptors (CT-R) in the area postrema (AP) is considered the main mechanism mediating amylin's anorectic effects [37][38][39]. The present results suggest that it is unlikely that the expression of CT-Rs in the AP is downregulated following 7-day infusion of physiological doses of amylin.…”