Amylin is a 37-amino
acid peptide hormone that is co-secreted with
insulin by pancreatic beta cells in response to feeding. We recently reported that
amylin potently reduces food intake,
body weight, and adiposity when delivered into the 3rd cerebral ventricle (i3vt) of rats. We have now infused i3vt a specific antagonist (
AC187) to ascertain the physiological relevance of central
amylin in the control of energy balance. After establishing the ability of i3vt
AC187 to block the anorexic effect of i3vt
amylin, we performed an experiment to examine the impact of acute inhibition of central
amylin signaling on feeding. Separate groups (n = 7/group) of ad lib-fed male Long Evans rats were given one bolus i3vt infusion of synthetic cerebrospinal fluid vehicle (CSF) or
AC187 (250 or 1000 pmol). Acute infusion of
AC187 tended to increase 1-h food intake and significantly elevated 4-h intake. Both the 250 and 1000 pmol doses produced significant increases as compared to CSF. In another experiment designed to tonically inhibit central
amylin signaling over an extended period, two other groups of rats (n = 6/group) received continuous i3vt infusion of CSF or 100 pmol/h
AC187 over 14 days via implantable osmotic pumps. Rats receiving
AC187 ate significantly more food over the 14-day infusion period relative to controls (CSF = 322 +/- 6 g,
AC187 = 360 +/- 12 g). Although
body weight was not significantly affected, body fat was increased by about 30% in the
AC187 rats, with no difference in lean tissue between the groups. Additionally, although fasting plasma
glucose did not differ between the CSF and
AC187 groups after 14 days of infusion, plasma
insulin was significantly elevated in the
AC187 rats. In summary, the present results document significant increases of food intake and body adiposity resulting from inhibition of central
amylin signaling. They are consistent with our hypothesis that CNS actions of endogenous
amylin contribute to the long-term regulation of energy balance.