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Summary   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 µg kg −1  d −1 ), murine leptin (125 µg 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.

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