Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein–coupled receptors resulting from the coexpression of a core receptor protein with receptor activity–modifying proteins, resulting in multiple receptor subtypes. Amylin’s major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.

The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet‐dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock‐out or knock‐in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit. Curr. Protoc. Pharmacol. 58:5.61.1‐5.61.18. © 2012 by John Wiley & Sons, Inc.

Roux-en-Y gastric bypass is the most effective therapy for morbid obesity. This study investigated how gastric bypass affects intake of and preference for high-fat food in an experimental (rat) study and within a trial setting (human). Proportion of dietary fat in gastric bypass patients was significantly lower 6 yr after surgery compared with patients after vertical-banded gastroplasty (P = 0.046). Gastric bypass reduced total fat and caloric intake (P < 0.001) and increased standard low-fat chow consumption compared with sham controls (P < 0.001) in rats. Compared with sham-operated rats, gastric bypass rats displayed much lower preferences for Intralipid concentrations > 0.5% in an ascending concentration series (0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%) of two-bottle preference tests (P = 0.005). This effect was demonstrated 10 and 200 days after surgery. However, there was no difference in appetitive or consummatory behavior in the brief access test between the two groups (P = 0.71) using similar Intralipid concentrations (0.005% through 5%). Levels of glucagon-like peptide-1 (GLP-1) were increased after gastric bypass as expected. An oral gavage of 1 ml corn oil after saccharin ingestion in gastric bypass rats induced a conditioned taste aversion. These findings suggest that changes in fat preference may contribute to long-term maintained weight loss after gastric bypass. Postingestive effects of high-fat nutrients resulting in conditioned taste aversion may partially explain this observation; the role of GLP-1 in mediating postprandial responses after gastric bypass requires further investigation.

Mechanisms underlying weight loss maintenance after gastric bypass are poorly understood. Our aim was to examine the effects of gastric bypass on energy expenditure in rats. Thirty diet-induced obese male Wistar rats underwent either gastric bypass (n = 14), sham-operation ad libitum fed (n = 8), or sham-operation body weight-matched (n = 8). Energy expenditure was measured in an open circuit calorimetry system. Twenty-four-hour energy expenditure was increased after gastric bypass (4.50 +/- 0.04 kcal/kg/h) compared with sham-operated, ad libitum fed (4.29 +/- 0.08 kcal/kg/h) and sham-operated, body weight-matched controls (3.98 +/- 0.10 kcal/kg/h, P < .001). Gastric bypass rats showed higher energy expenditure during the light phase than sham-operated control groups (sham-operated, ad libitum fed: 3.63 +/- 0.04 kcal/kg/h vs sham-operated, body weight-matched: 3.42 +/- 0.05 kcal/kg/h vs bypass: 4.12 +/- 0.03 kcal/kg/h, P < .001). Diet-induced thermogenesis was elevated after gastric bypass compared with sham-operated, body weight-matched controls 3 hours after a test meal (0.41% +/- 1.9% vs 10.5% +/- 2.0%, respectively, P < .05). The small bowel of gastric bypass rats was 72.1% heavier because of hypertrophy compared with sham-operated, ad libitum fed rats (P < .0001). Gastric bypass in rats prevented the decrease in energy expenditure after weight loss. Diet-induced thermogenesis was higher after gastric bypass compared with body weight-matched controls. Raised energy expenditure may be a mechanism explaining the physiologic basis of weight loss after gastric bypass.