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

Autor: Aaron P. Frank, Morvarid Kabir, Orison O. Woolcott, Rebecca L. Paszkiewicz, Malini S. Iyer, Roberta de Souza Santos, Richard N. Bergman, Deborah J. Clegg, Darko Stefanovski
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
Lipolysis
Morpholines
Drug Evaluation
Preclinical
Adipose tissue
030209 endocrinology & metabolism
Catalysis
Article
Inorganic Chemistry
lcsh:Chemistry
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Oxygen Consumption
Rimonabant
mitochondrial function
Receptor
Cannabinoid
CB1
Internal medicine
Adipocyte
medicine
Adipocytes
Glucose homeostasis
Animals
CB1R antagonist
Obesity
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Chemistry
Organic Chemistry
Antagonist
Correction
3T3-L1
General Medicine
3T3 Cells
Computer Science Applications
Mitochondria
030104 developmental biology
Endocrinology
Mitochondrial biogenesis
lcsh:Biology (General)
lcsh:QD1-999
beige adipocytes
Pyrazoles
medicine.drug
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 21, Iss 6639, p 6639 (2020)
Volume 21
Issue 18
ISSN: 1422-0067
Popis: 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.
Databáze: OpenAIRE
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