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Amylin/Leptin Synergy Is Absent in Extreme Obesity and Not Restored by Calorie Restriction-Induced Weight Loss in Rats J

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Amylin/Leptin Synergy Is Absent in Extreme Obesity and Not Restored by Calorie Restriction-Induced Weight Loss in Rats J Obesity Science & Practice doi: 10.1002/osp4.62 ORIGINAL ARTICLE Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats J. L. Trevaskis†, C. Wittmer, J. Athanacio, P. S. Griffin, D. G. Parkes and J. D. Roth‡ Summary 1Amylin Pharmaceuticals, San Diego, CA, USA; Objective Received 29 April 2016; revised 15 July Co-administration of amylin and leptin induces synergistic and clinically meaningful 2016; accepted 23 July 2016 (>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. Address for correspondence: James L. Trevaskis, PhD, MedImmune, One Methods MedImmune Way, Gaithersburg, MD 20878, USA. Sprague Dawley rats on high-fat diet (696 ± 8 g, n = 72) were randomized to three cohorts E-mail: [email protected] À À (C1–C3). Rats in C1 were administered vehicle, rat amylin (50 μgkg 1 d 1), murine leptin À1 À1 † (125 μgkg d ) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous Current address: MedImmune, Gaithersburg, MD, USA. minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 ± 0.3%, ‡Current address: Intercept Pharmaceuticals, 86.7 ± 2.8 g; C2) or severe (24.9 ± 0.3%, 172.7 ± 4.7 g; C3) weight loss, amylin and/or lep- San Diego, CA, USA. tin was administered as described. Results In C1, leptin did not alter weight, and amylin induced 40.2 ± 6.1 g weight loss (À6.0 ± 0.9%), which was not enhanced by leptin (44.4 ± 4.9 g, À6.1 ± 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, À1.3 ± 1.0%) rebounded to pre-restriction weight that was attenuated by amylin (29.2 ± 11.4 g, À6.2 ± 0.7%). Leptin did not enhance the effect of amylin (22.8 ± 11.7 g, À8.3 ± 1.5%). In C3, vehicle-treated and leptin-treated rats regained most of their weight (161.9 ± 11.8, À2.3 ± 0.8% and 144.6 ± 9.5 g, À2.3 ± 0.9%, respectively), which was attenuated by amylin (91.1 ± 16.8 g, À11.2 ± 0.7%), but not enhanced by leptin (83.0 ± 7.6 g, À10.7 ± 0.8%). Conclusions Extreme obesity associated with leptin resistance perturbs amylin/leptin weight loss syn- ergy in rats, which cannot be restored by pre-treatment weight loss. Keywords: Diabetes, obesity, synergy. Introduction with leptin-insufficient congenital or acquired generalized lipodystrophy. In leptin-deficient states like generalized Leptin, a hormone secreted by adipose tissue, has long lipodystrophy, metreleptin has been reported to improve been touted as a potential anti-obesity molecule (1). The the profound insulin resistance and other metabolic ab- role of endogenous leptin in the regulation of energy bal- normalities present in that population (5). However, in ance is clear, yet exogenously administered leptin has states like obesity, the phenomenon of leptin resistance remained intractable as a therapy for obesity (2). Leptin is uniformly observed and is felt to be a consequence in administration to leptin-deficient rodents and humans part of the endogenous hyperleptinemia associated with dramatically improves obesity and metabolic disease obesity (2,6). While the mechanism or molecular founda- (3,4), and recombinant human leptin (metreleptin) was re- tion of leptin resistance remains unknown, the potential cently approved as an adjunct to diet for use in individuals ability to restore leptin sensitivity in states of obesity- © 2016 The Authors Obesity Science & Practice published by John Wiley & Sons Ltd, World Obesity and The Obesity Society. Obesity Science & Practice 385 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 386 Amylin/leptin synergy set by pre-weight J. L. Trevaskis et al. Obesity Science & Practice associated leptin resistance remains an attractive area of Houston, TX, USA) and randomized to three cohorts research for anti-obesity pharmacotherapies (7). (each n = 24) based on body weight. Rats in cohort 1 Amylin is a peptide hormone co-secreted with insulin (C1) were subsequently randomized to four weight- from pancreatic β-cells, which has primary physiological matched groups (n = 6 per group) for vehicle or drug treat- roles in the regulation of glucose and energy balance via ment (described in the succeeding text). Remaining rats in its activity at specific receptors in the area postrema of cohorts 2 and 3 (C2 and C3) were subjected to 50% CR the hindbrain (8). In humans with obesity, the synthetic based on mean 24-h food intake for the previous 5 days amylin analogue pramlintide inhibited food intake and in- (average food intake for the whole group of rats was duced significant weight loss (9,10). Amylin has been 17.6 ± 0.3 g; rats in C2 and C3 were allocated 8.8 g of diet demonstrated to be one of the few molecules that is able per day, just prior to lights off). At this level of CR, body to restore leptin sensitivity in obesity. The co- weight loss of the rats began to plateau by day 5, so on administration of amylin and leptin (in rodents) or day 6, the degree of CR was increased to 75%, and rats pramlintide and metreleptin (in humans) elicited synergis- were allocated 4.4 g of diet per day and throughout the re- tic clinically meaningful effects on weight loss (11–14). mainder of the CR phase. On day 15 of CR when animals Leptin resistance, however, is not so easily, nor uniformly, had reached 12.4% body weight loss, rats in C2 were abolished. In studies in extremely diet-induced obese subjected to a second body composition assessment (DIO) rats (average body weight ~800 g), we reported that (EchoMRI), and on day 16, rats were randomized to four amylin/leptin synergy was less evident compared with weight-matched groups for vehicle or drug administra- more moderately DIO (average body weight ~500 g) rats tion. On day 34 of CR, the target weight loss of 25% (15). This was further reflected in the results of a 52-week was reached in the remaining C3 rats, and they were ad- blinded, placebo-controlled phase II study of ministered a body composition assessment (EchoMRI) pramlintide/metreleptin in which the most robust efficacy and randomized to vehicle or drug treatment groups was seen in patients with a body mass index less than based on body weight. 35 kg mÀ2 (16). As a means to potentially understand whether pramlintide/metreleptin could have therapeutic utility in Drug administration and plasma analysis the most obese subjects where the incidence and impact of weight-related comorbidities is most profound (17), we On day 0 (C1), day 16 (C2) or day 35 (C3) of the CR phase, investigated whether the loss of amylin-mediated leptin rats were implanted subcutaneously with two osmotic synergy in a state of extreme obesity could be rescued minipumps (Alzet, Cupertino, CA model 2ML4), delivering by weight loss induced via caloric restriction prior to either vehicle (50% dimethyl sulfoxide)/vehicle (sterile wa- μ À1 À1 pharmacotherapy. ter), amylin (50 gkg d )/vehicle (sterile water), leptin (125 μgkgÀ1 dÀ1)/vehicle (50% dimethyl sulfoxide) or À À À À Materials and methods amylin (50 μgkg 1 d 1)/leptin (125 μgkg 1 d 1) for 28 days. These doses were selected from a previous Animal experiments study that mapped amylin + leptin weight loss synergy across a range of doses using response surface method- All studies were approved by the Institutional Animal Care ology (12). Minipumps were prepared the day before im- and Use Committee at Amylin Pharmaceuticals, LLC in plantation and were incubated in sterile saline at 37 °C accordance with Animal Welfare Act guidelines. Animals overnight. Minipumps were implanted in the subscapular were housed individually in standard caging at 22 C in a space, one in either side of the spine, in sterile conditions 12-h light : dark cycle. Male Sprague Dawley rats (n = 85; with the rats under isoflurane anaesthesia. Following Charles River Laboratories, Wilmington, MA, USA) were minipump implantation, all animals were allowed ad pre-fattened on a high-fat diet (HFD; 32% kcal per fat; libitum access to HFD (D12266B, research diets). D12266B, Research Diets, Brunswick, NJ, USA) at Vehicle or drug was administered via minipump for Charles River from 6 weeks of age until 12 weeks of age. 28 days. Body weight and food intake were measured Upon arrival, the mean body weight of the animals was weekly. 441 ± 4 g, and rats were maintained on the same diet for On day 28 of drug treatment, rats were administered a fi- a further 22 weeks (34 weeks of age). At this time, the final nal body composition assessment (EchoMRI), then eu- study population (n = 72) was selected, and mean body thanized via anaesthetic (isoflurane) overdose and weight was 696 ± 8 g. cardiac blood collected via cardiac puncture. Blood was The final population was subjected to a body composi- collected into a heparin sodium-coated tube, and plasma tion assessment (EchoMRI, Echo Medical Systems, glucose, triglycerides and total cholesterol were © 2016 The Authors Obesity Science & Practice published by John Wiley & Sons Ltd, World Obesity and The Obesity Society. Obesity Science & Practice Obesity Science & Practice Amylin/leptin synergy set by pre-weight J. L.
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