Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development.
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.
1Department of Food Science, College of Agricultural Center, Louisiana State University, Baton Rouge, LA; 2Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA; 3Columbia University, New York, NY; 4Department of Biological Science, College of Sciences, Louisiana State University, Baton Rouge, LA; 5Department of Environment, School of Life Sciences, Fudan University, Shanghai, China; and 6University of California, Davis One Shields Avenue Davis, CA.
Jolene
J
Zheng
Joseph R
JR
Vasselli
Jason F
JF
King
Michael L
ML
King
Wenqian
W
We
Zachary
Z
Fitzpatrick
William D
WD
Johnson
John W
JW
Finley
Roy J
RJ
Martin
Michael J
MJ
Keenan
Frederic M
FM
Enright
Frank L
FL
Greenway
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects; D001621:Betahistine / Q000008:administration & dosage / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D004195:Disease Models, Animal; D015195:Drug Design; D009765:Obesity / Q000139:chemically induced / Q000517:prevention & control*; D000077152:Olanzapine; D011480:Protease Inhibitors / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects
D019440:Anti-Obesity Agents; D014150:Antipsychotic Agents; D011480:Protease Inhibitors; D001569:Benzodiazepines; D002334:Carnitine O-Palmitoyltransferase; D000077152:Olanzapine; D001621:Betahistine