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Research ArticleBehavioral Pharmacology

Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

Anna Thorsø Larsen, Nina Sonne, Kim V. Andreassen, Morten A. Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics May 2020, 373 (2) 269-278; DOI: https://doi.org/10.1124/jpet.119.263400
Anna Thorsø Larsen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Nina Sonne
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Kim V. Andreassen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Morten A. Karsdal
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Kim Henriksen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Abstract

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible.

SIGNIFICANCE STATEMENT Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity.

Footnotes

    • Received October 23, 2019.
    • Accepted February 10, 2020.
  • ↵1 A.T.L. and N.S. contributed equally to this work.

  • https://doi.org/10.1124/jpet.119.263400.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 2
1 May 2020
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Research ArticleBehavioral Pharmacology

KBP-088 Improves Food Preference Dependent on Dose Frequency

Anna Thorsø Larsen, Nina Sonne, Kim V. Andreassen, Morten A. Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics May 1, 2020, 373 (2) 269-278; DOI: https://doi.org/10.1124/jpet.119.263400

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Research ArticleBehavioral Pharmacology

KBP-088 Improves Food Preference Dependent on Dose Frequency

Anna Thorsø Larsen, Nina Sonne, Kim V. Andreassen, Morten A. Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics May 1, 2020, 373 (2) 269-278; DOI: https://doi.org/10.1124/jpet.119.263400
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