Amylin - Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity

Abstract

Background: 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.

Scope of review: 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.

Conclusion: We propose here that the effects of amylin may be homeostatic and hedonic in nature.

Keywords: Amylin; Analog; CGRP; Hedonic; Homeostatic; Reward.

Figure 1

(A) Cumulative energy intake after saline or amylin (5 pmol; i3vt injection at dark onset in undeprived rats) in rats maintained for three weeks on Ensure^® cacao plus chow or on chow only; n = 18–19/group. Cumulative energy intake after saline or amylin (5 pmol; i3vt injection at dark onset in undeprived rats (B, n = 10/group) or 5 μg/kg s.c. injection at dark onset after 3 h-food deprivation (C, n = 32/group), respectively) in rats maintained for three days on Ensure^® cacao only or on chow only; (D) Cumulative energy intake after saline or amylin (5 pmol; i3vt injection at dark onset in undeprived rats) in rats maintained for three days on Ensure^® cacao, a pelleted high-fat diet, or chow only; n = 6–10/group. Values are mean ± SEM, symbols denote significant differences between saline- and amylin-treated groups within the respective diet groups; *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 2

(A) Linoleic acid (LA)-induced pramlintide production in HT1080 cells at 48 h. Non-transfected cells were incubated with transfection solution without plasmids, non-treated cells were incubated with transfection solution and 250 ng pKR135 (LSR construct) + 250 ng pKR146 (pramlintide construct) or 250 ng pKR135 + 500 ng pKR146, and treated cells were transfected with 250 ng pKR135 + 250 ng pKR146 or 250 ng pKR135 + 500 ng pKR146 and treated daily with 100 μM linoleic acid. Values are mean ± SEM, n = 4/group. Data with differing superscripts differ from each other by P = 0.05 or less when assessed by two way ANOVA followed by post-hoc Bonferroni t-test. LSR-construct alginate beads or LSR-pramlintide alginate beads were then injected i.p in male Sprague–Dawley rats fed HF 60% (B) Cumulative body weight gain over the 12-day period. *P < 0.05 after a two-way repeated measures ANOVA and post-hoc Bonferroni test. (C) Food intake in kcal after a 4 h meal test on day 3 and (D) leptin-induced anorexia at 4 h and 24 h tested in a cross-over design on day 5 and 7 post-injection. Values are mean ± SEM, n = 6/group, **P < 0.01 or less, using unpaired Student's t-test.