Modeling energy intake and body weight effects of a long-acting amylin analogue
The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens. Overall, 6 pharmacodynamic (PD) studies including a total of 173 rats were considered in this evaluation. Treatment caused a dose-dependent reduction in EI and BW, although multiple dosing indicated the development of tolerance over time. This behavior could be adequately described by a population model including homeostatic feedback of EI and a turnover model describing the relationship between EI and BW. The model was evaluated by testing its ability to predict BW loss in a toxicology study and was utilized to improve the understanding of dosing regimens for obesity therapy. As such, the model proved to be a valuable tool for the design and interpretation of rodent studies used in anti-obesity drug development.
KeywordsModel-informed drug discovery Obesity Energy intake Amylin analogue Tolerance
The authors would like to thank Hermann Rapp for valuable discussions and Dr. Arno Kalkuhl for providing us with the toxicology study data. Moreover, we like to thank Sidsel Larsen, Charlotte Holtoft, Arne Lindhardt Jensen, Jessica Bedenik and Christina Doll for excellent technical support.
All authors provided critical review of drafts of the manuscript, and read and approved the final version. AB and JB contributed equally to the development of the model, to the interpretation of the modeling results and writing the manuscript. All other authors contributed to the design of the study and interpretation of the data, and supported and reviewed the model compilation.
Compliance with ethical standards
Conflict of interest
Jens M. Borghardt, Wolfgang Rist, Stefan Scheuerer and Tamara Baader-Pagler are employees of Boehringer Ingelheim Pharma GmbH & Co KG. Jolanta Skarbaliene and Maria A. Deryabina are employees of Zealand Pharma A/S. Annika Brings was an employee of Boehringer Ingelheim Pharma GmbH & Co KG at the time of the manuscript creation.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 2.Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295(7):761–775. https://doi.org/10.1001/jama.295.7.761 CrossRefPubMedGoogle Scholar
- 4.James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine trial of obesity reduction and maintenance. Lancet 356(9248):2119–2125CrossRefPubMedGoogle Scholar
- 7.Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, Koda JE, Weyer C (2009) Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 17(9):1736–1743. https://doi.org/10.1038/oby.2009.184 CrossRefGoogle Scholar
- 9.Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD (2008) Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA 105(20):7257–7262. https://doi.org/10.1073/pnas.0706473105 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Merce R, Holenz J, Vrang N, Sorensen RV, Heal D, Buschmann H, Pauwels PJ (2006) Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats. Br J Pharmacol 148(7):973–983. https://doi.org/10.1038/sj.bjp.0706807 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Madsen AN, Hansen G, Paulsen SJ, Lykkegaard K, Tang-Christensen M, Hansen HS, Levin BE, Larsen PJ, Knudsen LB, Fosgerau K, Vrang N (2010) Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol 206(3):287–296. https://doi.org/10.1677/JOE-10-0004 CrossRefPubMedGoogle Scholar
- 15.Roth JD, Hughes H, Kendall E, Baron AD, Anderson CM (2006) Antiobesity effects of the beta-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 147(12):5855–5864. https://doi.org/10.1210/en.2006-0393 CrossRefPubMedGoogle Scholar
- 16.Mack C, Wilson J, Athanacio J, Reynolds J, Laugero K, Guss S, Vu C, Roth J, Parkes D (2007) Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight. Am J Physiol Regul Integr Comp Physiol 293(5):R1855–R1863. https://doi.org/10.1152/ajpregu.00297.2007 CrossRefPubMedGoogle Scholar
- 17.Roth JD, Hughes H, Coffey T, Maier H, Trevaskis JL, Anderson CM (2007) Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats. Am J Physiol Endocrinol Metab 293(4):E1112–E1117. https://doi.org/10.1152/ajpendo.00395.2007 CrossRefPubMedGoogle Scholar
- 24.Roth JD, Coffey T, Jodka CM, Maier H, Athanacio JR, Mack CM, Weyer C, Parkes DG (2007) Combination therapy with amylin and peptide YY[3-36] in obese rodents: anorexigenic synergy and weight loss additivity. Endocrinology 148(12):6054–6061. https://doi.org/10.1210/en.2007-0898 CrossRefPubMedGoogle Scholar
- 25.Isaksson B, Wang F, Permert J, Olsson M, Fruin B, Herrington MK, Enochsson L, Erlanson-Albertsson C, Arnelo U (2005) Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis. Pancreatology 5(1):29–36. https://doi.org/10.1159/000084488 CrossRefPubMedGoogle Scholar
- 40.Gennemark P, Jansson-Lofmark R, Hyberg G, Wigstrand M, Kakol-Palm D, Hakansson P, Hovdal D, Brodin P, Fritsch-Fredin M, Antonsson M, Ploj K, Gabrielsson J (2013) A modeling approach for compounds affecting body composition. J Pharmacokinet Pharmacodyn 40(6):651–667. https://doi.org/10.1007/s10928-013-9337-x CrossRefPubMedGoogle Scholar
- 41.Selimkhanov J, Thompson WC, Patterson TA, Hadcock JR, Scott DO, Maurer TS, Musante CJ (2016) Evaluation of a mathematical model of rat body weight regulation in application to caloric restriction and drug treatment studies. PLoS ONE 11(5):e0155674. https://doi.org/10.1371/journal.pone.0155674 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rossner S, Van Gaal L, Astrup A, Investigators NN (2014) Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 38(5):689–697. https://doi.org/10.1038/ijo.2013.149 CrossRefGoogle Scholar
- 48.Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, Burns C, Lush CW, Weyer C (2007) Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab 92(8):2977–2983. https://doi.org/10.1210/jc.2006-2003 CrossRefPubMedGoogle Scholar
- 49.Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR (2012) The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 62(5–6):1916–1927. https://doi.org/10.1016/j.neuropharm.2011.12.022 CrossRefPubMedGoogle Scholar
- 50.Hjuler ST, Gydesen S, Andreassen KV, Pedersen SL, Hellgren LI, Karsdal MA, Henriksen K (2016) The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity (Silver Spring) 24(8):1712–1722. https://doi.org/10.1002/oby.21563 CrossRefGoogle Scholar
- 56.Gennemark P, Tragardh M, Linden D, Ploj K, Johansson A, Turnbull A, Carlsson B, Antonsson M (2017) Translational modeling to guide study design and dose choice in obesity exemplified by AZD1979, a melanin-concentrating hormone receptor 1 antagonist. CPT 6(7):458–468. https://doi.org/10.1002/psp4.12199 Google Scholar