Amylin and ingestive behaviour

Amylin and ingestive behaviour

Islet amyloid polypeptide or amylin, is co-secreted with insulin from pancreatic B-cells. Whereas with regard to food intake, insulin functions mainly as an adiposity signal and glucagon functions mainly as a satiety signal, amylin has characteristics of both kinds of signal. Like insulin, plasma amylin levels are low during fasting and increase during meals and following glucose administration, and the levels are all directly proportional to body fat. Amylin and insulin are normally co-secreted in a fixed molecular ratio (insulin to amylin) of between ten and one hundred. Obesity, diabetes mellitus, pancreatic cancer and certain pharmacological interventions all tend to increase the amount of amylin relative to insulin.

(a) Amylin as a satiety signal

Eating results in a rapid increase in plasma amylin that is directly proportional to meal size (Butler et al. 1990; Moore & Cooper 1991; Young & Denaro 1998). Administration of exogenous amylin prior to a meal dose-dependently reduces food intake in rats and mice (Chance et al. 1991; Morley & Flood 1991; Lutz et al. 1994, 1995; Morley et al. 1994; Arnelo et al. 1996a), mainly due to a reduction in meal size (Lutz et al. 1995, 2001b; Reidelberger et al. 2002; Mollet et al. 2004), without producing a conditioned taste aversion (Chance et al. 1992; Lutz et al. 1995; Morley et al. 1997; Asarian et al. 1998; Rushing et al. 2002). The effect of exogenous amylin on meal pattern is therefore similar to that of CCK. As discussed below, plasma amylin is thought to function as a satiety signal by accessing receptors in the AP in the hindbrain, a region with a relatively permeable blood–brain barrier. Nonetheless, some plasma amylin probably does enter the brain via facilitated transport through the blood–brain barrier (Banks et al. 1995), and when amylin is administered directly into the lateral or 3rd-cerebral ventricle, it elicits a potent and long-lasting anorectic effect at very low doses (Rushing et al. 2002). Consistent with this, blockade of central amylin receptors produces a long-lasting increase in food intake, body weight and body adiposity (Rushing et al. 2001).

(b) Disruption of amylin signalling

Several amylin antagonists are available (e.g. amylin 8-37, AC 253 and AC 187), and when administered prior to meals either systemically or directly into the AP, each attenuates the anorectic action of exogenous amylin (Lutz et al. 1996, 1997b, 2000; Mollet et al. 2004; Reidelberger et al. 2004) and increases food intake when administered alone (Grabler & Lutz 2004; Mollet et al. 2004; Reidelberger et al. 2004). These data strongly imply a physiological role of endogenous amylin in the regulation of food intake, specifically in the regulation of meal size. Consistent with this, mice lacking amylin have a significantly increased rate of body weight gain and slightly increased cumulative food intake relative to controls (Gebre-Medhin et al. 1997, 1998; Lutz 2005). Little is known of the post-receptor intracellular signalling mechanisms elicited by amylin, although its anorectic action has been linked to the formation of cGMP in the AP (Riediger et al. 2001; Becskei et al. 2004).


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