Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats

Objective Co-administration of amylin and leptin induces synergistic and clinically meaningful (> 10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats. Methods Sprague Dawley rats on high-fat diet (696 +/- 8 g, n = 72) were randomized to three cohorts (C1-C3). Rats in C1 were administered vehicle, rat amylin (50 mu g kg(-1) d(-1)), murine leptin (125 mu g kg(-1) d(-1)) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 +/- 0.3%, 86.7 +/- 2.8 g; C2) or severe (24.9 +/- 0.3%, 172.7 +/- 4.7 g; C3) weight loss, amylin and/or leptin was administered as described. Results In C1, leptin did not alter weight, and amylin induced 40.2 +/- 6.1 g weight loss (-6.0 +/- 0.9%), which was not enhanced by leptin (44.4 +/- 4.9 g, +/- 6.1 +/- 0.8%). In C2, vehicle-treated (75.1 +/- 7.8 g weight change from start of treatment, 1.1 +/- 0.8% difference from start of pre-CR phase) and leptin-treated rats (68.6 +/- 9.2 g, -1.3 +/- 1.0%) rebounded to pre-restriction weight that was attenuated by amylin (29.2 +/- 11.4 g, -6.2 +/- 0.7%). Leptin did not enhance the effect of amylin (22.8 +/- 11.7 g, -8.3 +/- 1.5%). In C3, vehicle-treated and leptin-treated rats regained most of their weight (161.9 +/- 11.8, -2.3 +/- 0.8% and 144.6 +/- 9.5 g, -2.3 +/- 0.9%, respectively), which was attenuated by amylin (91.1 +/- 16.8 g, -11.2 +/- 0.7%), but not enhanced by leptin (83.0 +/- 7.6 g, -10.7 +/- 0.8%). Conclusions Extreme obesity associated with leptin resistance perturbs amylin/leptin weight loss synergy in rats, which cannot be restored by pre-treatment weight loss.