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
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 improv...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/18/6639 |
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| author | Rebecca L. Paszkiewicz Richard N. Bergman Roberta S. Santos Aaron P. Frank Orison O. Woolcott Malini S. Iyer Darko Stefanovski Deborah J. Clegg Morvarid Kabir |
| author_facet | Rebecca L. Paszkiewicz Richard N. Bergman Roberta S. Santos Aaron P. Frank Orison O. Woolcott Malini S. Iyer Darko Stefanovski Deborah J. Clegg Morvarid Kabir |
| author_sort | Rebecca L. Paszkiewicz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:25:53Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:25:53Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-db02d6c01c294d78b0c19e5e477573282023-11-20T13:18:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012118663910.3390/ijms21186639A 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 AvoidedRebecca L. Paszkiewicz0Richard N. Bergman1Roberta S. Santos2Aaron P. Frank3Orison O. Woolcott4Malini S. Iyer5Darko Stefanovski6Deborah J. Clegg7Morvarid Kabir8Sports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USASchool of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAThe College of Nursing and Health Professions, Drexel University, Philadelphia, PA 19104, USASports Spectacular Diabetes and Obesity Wellness and Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USAWith 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.https://www.mdpi.com/1422-0067/21/18/6639beige adipocyteslipolysisCB1R antagonistmitochondrial functionobesity |
| spellingShingle | Rebecca L. Paszkiewicz Richard N. Bergman Roberta S. Santos Aaron P. Frank Orison O. Woolcott Malini S. Iyer Darko Stefanovski Deborah J. Clegg Morvarid Kabir 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 beige adipocytes lipolysis CB1R antagonist mitochondrial function obesity |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | beige adipocytes lipolysis CB1R antagonist mitochondrial function obesity |
| url | https://www.mdpi.com/1422-0067/21/18/6639 |
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