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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.

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OBJECTIVE:To identify the role of hyperleptinaemia in mediating the effects of early postnatal overfeeding in a rat strain known to be prone to manipulations of the early environment which result in predispositions for obesity and associated metabolic and cardiovascular disturbance in later life. DESIGN: Wistar rats were reared in normal litters (NL, 10 -12 pups) or small litters (SL, four pups) from postnatal day 3 and killed for determination of body composition and plasma leptin and insulin concentrations on day 7 or day 21 after having been treated with recombinant leptin (2Â50 (pmol=g)=day) or saline from day 1. RESULTS: Rearing in SL doubled the body fat content and plasma leptin levels in comparison to NL pups by 21 days of age. Under leptin-treatment throughout suckling age, NL pups remained leptin responsive, ie the difference in body fat content was progressively reduced relative to the controls. Until 7 days of age, despite the body fat content of untreated SL pups being 2-fold higher and their plasma leptin level 7-fold higher than that of NL pups, leptin treatment caused the same percentage decreases in body fat in SL than in NL pups. But in contrast to NL pups, the SL pups became leptin resistant thereafter. Plasma insulin levels in 7-day-old leptin-treated SL pups were 3-fold higher than in untreated littermates and 5-fold higher than in the NL groups. CONCLUSION: Prophylactic leptin treatment does not prevent hyperinsulinaemia and excessive fat deposition in SL pups. On the other hand, selective hyperleptinaemia during suckling age does not trigger leptin resistance and obesity in NL pups. Rather than hyperleptinaemia per se, other factors associated with early postnatal overnutrition, for example, the concurrent hyperinsulinaemia, seem to play a pivotal role for the development of leptin-resistance and life-long obesity risk in SL rats.

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