Amylin Acts in the Central Nervous System to Increase Sympathetic Nerve Activity

Abstract

The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function.