title: Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats.
abstract: 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-1d-1), murine leptin (125 µg kg-1d-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.
authors.affiliation: Present address: MedImmune, Gaithersburg MD USA.
authors.forename: J L
authors.identifier: 0000-0002-5356-6118
authors.initials: JL
authors.lastname: Trevaskis
authors.affiliation: Amylin Pharmaceuticals San Diego CA USA.
authors.forename: C
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Amylin Pharmaceuticals San Diego CA USA.
authors.forename: J
authors.initials: J
authors.lastname: Athanacio
authors.affiliation: Amylin Pharmaceuticals San Diego CA USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Griffin
authors.affiliation: Amylin Pharmaceuticals San Diego CA USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Parkes
authors.affiliation: Present address: Intercept Pharmaceuticals San Diego CA USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Roth
keywords: Diabetes; obesity; synergy