Journal article
A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided
International journal of molecular sciences, v 21(18), pp 1-15
01 Sep 2020
PMID: 32927872
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
With the increased prevalence of obesity and related co-morbidities, such as type 2 diabetes (T2D), worldwide, improvements in pharmacological treatments are necessary. The brain- and peripheral-cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been shown to induce weight loss and improve glucose homeostasis. We have previously demonstrated that RIM promotes adipose tissue beiging and decreased adipocyte cell size, even during maintenance on a high-fat diet. Given the adverse side-effects of brain-penetrance with RIM, in this study we aimed to determine the site of action for a non-brain-penetrating CB1R antagonist AM6545. By using in vitro assays, we demonstrated the direct effects of this non-brain-penetrating CB1R antagonist on cultured adipocytes. Specifically, we showed, for the first time, that AM6545 significantly increases markers of adipose tissue beiging, mitochondrial biogenesis, and lipolysis in 3T3-L1 adipocytes. In addition, the oxygen consumption rate (OCR), consisting of baseline respiratory rate, proton leak, maximal respiratory capacity, and ATP synthase activity, was greater for cells exposed to AM6545, demonstrating greater mitochondrial uncoupling. Using a lipolysis inhibitor during real-time OCR measurements, we determined that the impact of CB1R antagonism on adipocytes is driven by increased lipolysis. Thus, our data suggest the direct role of CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of focus on peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and T2D.
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Details
- Title
- A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided
- Creators
- Rebecca L. Paszkiewicz - Cedars-Sinai Medical CenterRichard N. Bergman - Cedars-Sinai Medical CenterRoberta S. Santos - College Station Medical CenterAaron P. Frank - Cedars-Sinai Medical CenterOrison O. Woolcott - Cedars-Sinai Medical CenterMalini S. Iyer - Cedars-Sinai Medical CenterDarko Stefanovski - University of PennsylvaniaDeborah J. Clegg - Drexel UniversityMorvarid Kabir - Cedars-Sinai Medical Center
- Publication Details
- International journal of molecular sciences, v 21(18), pp 1-15
- Publisher
- Mdpi
- Number of pages
- 15
- Grant note
- R01-DK029867 / NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000580735400001
- Scopus ID
- 2-s2.0-85090666586
- Other Identifier
- 991019357772704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary