Firing Up Brown Fat with Brain Amylin

Abstract

The search for valuable antiobesity therapies is an urgent necessitynotonly indevelopedbutalsoindevelopingcountries (1). To date, bariatric surgery is the most effective strategy to reduce and maintain weight loss in obese individuals, and therefore much effort is being made to depict which gastrointestinal (GI) signals are involved in this process and their mechanisms of action (2). Among the large list of GI factors controlling energy balance, amylin is one of the most attractive. Amylin is a 37-amino acid peptide hormone that is cosecreted with insulin by pancreatic -cells in response to nutrient ingestion, helping to maintain glucose homeostasis (3). Amylin has been involved in a wide range of biological actions, including slow gastric emptying (4), suppression of nutrient-stimulated glucagon secretion (5), and suppression of food intake (6). Importantly, amylin maintains its antiobesity action in obese rats (7) and is able to restore leptin sensitivity in obese rodents and humans (8). In addition, combined amylin and leptin treatment has synergistic actions in obese animals (9), an interaction that does not occur with other GI signals such as glucagon like peptide-1 (10). The body weight loss caused by the coadministration of leptin and amylin cannot be entirely explained by the suppression in food intake (7), suggesting that alternative metabolic pathways are involved in amylin’s control of body weight. Those food intake–independent metabolic actions seem to be, at least partially, mediated by the brain, because chronic central infusion of amylin reduced the respiratory exchange ratio and increased body temperature (11). Mice overexpressing neuronal RAMP1 (receptor activity–modifying protein 1, the amylin receptor) also show higher energy expenditure as indicated by increased oxygen consumption, body temperature, sympathetic tone, and expression of thermogenic markers in brown adipose tissue (BAT) (12). In this issue of Endocrinology, Rahmouni and colleagues (13) move our neurobiological understanding significantly forwardbydemonstratingadirect linkbetweenbrainamylin and BAT thermogenesis through the sympathetic nervous system (SNS). Specifically they show that besides its role on feeding, amylin increases the activity of the SNS, leading to increasedBATthermogenesis andweight loss.Theyusemice and direct multifiber sympathetic nerve recording to unequivocally demonstrate that intracerebroventricular injection of amylin promotes a dose-dependent increase in the sympathetic nerve activity subserving BAT, which subsequently elevates body temperature. The connotation of these data is exemplified by several mechanistic findings, which demonstrate the crucial effect of the amylin-SNS-BAT axis. First, intracerebroventricular pretreatment with the amylin receptor antagonist AC187 totally blunted the BAT SNA response induced by central amylin (13). Second, the amylin response was boosted in transgenic mice overexpressing the amylin receptor subunit RAMP1 in the central nervous system (13). Finally, central amylin promoted a marked activation (measured as c-Fos immunoreactivity) in key hypothalamic and brainstem sites such as the anterior hypothalamic area (AHA), the dorsomedial nucleus of the hypothalamus (DMH), the area postrema, and the nucleus of the tractus solitarius, all of which are known to modulate energy balance (14). This specific pattern of activation also opens up some interesting questions about the neuronal, cellular, and molecular mechanisms mediating amylin’s action. Although a role for the AHA and the DMH in regulating BAT has been known since the 1980s (15), only recently have reports started to address the molecular mech-