1. Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development
- Author
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Frank L. Greenway, Zachary L. Fitzpatrick, Michael J. Keenan, John W. Finley, Joseph R. Vasselli, Michael L. King, Jolene Zheng, Frederic M. Enright, Jason F. King, Roy J. Martin, William D. Johnson, and Wenqian We
- Subjects
0301 basic medicine ,Pharyngeal pumping ,medicine.medical_treatment ,Pharmacology ,Article ,Benzodiazepines ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Lipid oxidation ,medicine ,Animals ,Protease Inhibitors ,Pharmacology (medical) ,Obesity ,Caenorhabditis elegans ,Protease ,Carnitine O-Palmitoyltransferase ,biology ,business.industry ,General Medicine ,biology.organism_classification ,Up-Regulation ,Atazanavir ,Disease Models, Animal ,030104 developmental biology ,Adipose Tissue ,Mechanism of action ,Olanzapine ,Drug Design ,Ritonavir ,Anti-Obesity Agents ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Antipsychotic Agents ,Betahistine ,medicine.drug - Abstract
The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine–olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 μg/mL) increased the IFD (12.1 ± 0.1%, P < 0.02), which was blocked by betahistine (763 μg/mL, 39.3 ± 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions.
- Published
- 2016