Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and body weight seen in preclinical and clinical studies. Amylin activates specific receptors, a portion of which it shares with calcitonin gene-related peptide (CGRP). Amylin's role in the control of energy metabolism relates to its satiating effect, but recent data indicate that amylin may also affect hedonic aspects in the control of eating, including a reduction of the rewarding value of food. Recently, several amylin-based peptides have been characterized. Pramlintide (Symlin®) is currently the only one being used clinically to treat type 1 and type 2 diabetes. However other amylin analogs with improved pharmacokinetic properties are being considered as anti-obesity treatment strategies. Several other studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents. This review will briefly summarize amylin physiology and pharmacology and then focus on amylin's role in food reward and the effects of amylin analogs in pre-clinical testing for anti-obesity drugs. We propose here that the effects of amylin may be homeostatic and hedonic in nature.

Amylin acts acutely via the area postrema to reduce food intake and body weight, but it also interacts with leptin over longer periods of time, possibly via the ventromedial hypothalamus (VMH), to increase leptin signaling and phosphorylation of STAT3. We postulated that amylin enhances VMH leptin signaling by inducing interleukin (IL)-6, which then interacts with its gp130 receptor to activate STAT3 signaling and gene transcription downstream of the leptin receptor. We found that components of the amylin receptor (RAMPs1–3, CTR1a,b) are expressed in cultured VMH astrocytes, neurons, and microglia, as well as in micropunches of arcuate and ventromedial hypothalamic nuclei (VMN). Amylin exposure for 5 days increased IL-6 mRNA expression in VMH explants and microglia by two- to threefold, respectively, as well as protein abundance in culture supernatants by five- and twofold, respectively. Amylin had no similar effects on cultured astrocytes or neurons. In rats, 5 days of amylin treatment decreased body weight gain and/or food intake and increased IL-6 mRNA expression in the VMN. Similar 5-day amylin treatment increased VMN leptin-induced phosphorylation of STAT3 expression in wild-type mice and rats infused with lateral ventricular IgG but not in IL-6 knockout mice or rats infused with ventricular IL-6 antibody. Lateral ventricular infusion of IL-6 antibody also prevented the amylin-induced decrease of body weight gain. These results show that amylin-induced VMH microglial IL-6 production is the likely mechanism by which amylin treatment interacts with VMH leptin signaling to increase its effect on weight loss.

Key points: Proteins are more satiating than fats or lipids. Proteins are built by the 20 proteogenic amino acids. Here, we identified l‐arginine, l‐lysine and l‐glutamic acid as the most potent anorectic amino acids in rats. l‐Arginine and l‐glutamic acid require intact neurons in the area postrema to inhibit food intake, whereas l‐lysine requires intact afferent fibres of the vagus nerve. All three mediate their effect by the blood stream. All three amino acids induce gastric distension by delaying gastric emptying and inducing secretion. However, the gastric phenotype does not mediate the anorectic response. These results unravel amino acid‐specific mechanisms regulating digestion and eating behaviour and thereby contribute to the understanding of nutrient sensing in vivo. Abstract  To maintain nutrient homeostasis the central nervous system integrates signals that promote or inhibit eating. The supply of vital amino acids is tuned by adjusting food intake according to its dietary protein content. We hypothesized that this effect is based on the sensing of individual amino acids as a signal to control food intake. Here, we show that food intake was most potently reduced by oral l‐arginine (Arg), l‐lysine (Lys) and l‐glutamic acid (Glu) compared to all other 17 proteogenic amino acids in rats. These three amino acids induced neuronal activity in the area postrema and the nucleus of the solitary tract. Surgical lesion of the area postrema abolished the anorectic response to Arg and Glu, whereas vagal afferent lesion prevented the response to Lys. These three amino acids also provoked gastric distension by differentially altering gastric secretion and/or emptying. Importantly, these peripheral mechanical vagal stimuli were dissociated from the amino acids’ effect on food intake. Thus, Arg, Lys and Glu had a selective impact on food processing and intake suggesting them as direct sensory input to assess dietary protein content and quality in vivo. Overall, this study reveals novel amino acid‐specific mechanisms for the control of food intake and of gastrointestinal function.

Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin is a physiological control of meal-ending satiation, and it limits the rate of gastric emptying and reduces the secretion of pancreatic glucagon, in particular in postprandial states. The physiological effects of amylin and its analogs are mediated by direct brain activation, with the caudal hindbrain playing the most prominent role. The clarification of the structure of amylin receptors, consisting of the calcitonin core receptor plus receptor-activity modifying proteins, aided in the development of amylin analogs with a broad pharmacological profile. The general interest in amylin physiology and pharmacology was boosted by the finding that amylin is a sensitizer to the catabolic actions of leptin. Today, amylin derived analogs are considered to be among the most promising approaches for the pharmacotherapy against obesity. At least in conjunction with insulin, amylin analogs are also considered important treatment options in diabetic patients, so that new drugs may soon be added to the only currently approved compound pramlintide (Symlin^®). This review provides a brief summary of the physiology of amylin’s mode of actions and its role in the control of the metabolism, in particular energy intake and glucose metabolism.