Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes
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OBJECTIVE: Cannabinoid type 1 (CB1) receptor blockade decreases body weight and adiposity in obese subjects; however, the underlying mechanism is not yet fully understood. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) induces mitochondrial biogenesis and function in adipocytes. This study was undertaken to test whether CB1 receptor blockade increases the espression of eNOS and mitochondrial biogenesis in white adipocytes. RESEARCH DESIGN AND METHODS: We examined the effects on eNOS and mitochondrial biogenesis of selective pharmacological blockade of CB1 receptors by SR141716 (rimonabant) in mouse primary white adipocytes. We also examined eNOS expression and mitochondrial biogenesis in white adipose tissue (WAT) and isolated mature white adipocytes of CB1 receptor-deficient (CB1(-/-)) and chronically SR141716-treated mice on either a standard or high-fat diet. RESULTS: SR141716 treatment increased eNOS expression in cultured white adipocytes. Moreover, SR141716 increased mitochondrial DNA amount, mRNA levels of genes involved in mitochondrial biogenesis, and mitochondrial mass and function through eNOS induction, as demonstrated by reversal of SR141716 effects by small interfering RNA-mediated decrease in eNOS. While high-fat diet-fed wild-type mice showed reduced eNOS expression and mitochondrial biogenesis in WAT and isolated mature white adipocytes, genetic CB1 receptor deletion or chronic treatment with SR141716 restored these parameters to the levels observed in wild-type mice on the standard diet, an effect linked to the prevention of adiposity and body weight increase. CONCLUSIONS: CB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat diet-induced fat accumulation, without concomitant changes in food intake.
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NOS3 is expressed at highest relative abundance in vascular endothelium, but is also found in neurons, epithelial cells, cardiomyocytes, adipocytes, and hepatocytes.
“NOS3 (commonly called endothelial NOS or eNOS) is expressed to highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67, 68] and hepatocytes [69-71].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [68]
Nitric oxide production by the endothelial nitric oxide synthase has also been linked to enhanced adipose tissue mitochondrial biogenesis and prevention of high-fat diet-induced obesity.
“Nitric oxide production by the endothelial nitric oxide synthase has also been linked to enhanced adipose tissue mitochondrial biogenesis and prevention of high-fat dietinduced obesity (200).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [200]
Mitochondrial levels in white adipocytes are also increased in response to adrenergic stimulation, β-3 agonists, and CB1 blockade in mice, again in parallel with enhanced insulin sensitivity.
“Mitochondrial levels in white adipocytes are also increased in response to adrenergic stimulation, -3 agonists, and CB1 blockade in mice (195,199,200), again in parallel with enhanced insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [200]
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“highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67,68] and hepatocytes [69–71].”
BackgroundVettor, R., Valerio, A., Ragni, M., Trevellin, E., Granzotto, M., Olivieri, M., Tedesco, L., Ruocco, C., Fossati, A., Fabris, R., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00617.2013 · Cited by 132 · see citing works
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- Authors
- Tedesco, L., Valerio, A., Cervino, C., Cardile, A., Pagano, C., Vettor, R., Pasquali, R., Carruba, M. O., Marsicano, G., Lutz, B., Pagotto, U., & Nisoli, E.
- Affiliations
- University of Milan (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- University of Padua (IT)
- Université de Bordeaux (FR)
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Nisoli, Enzo
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-08-01
- Volume
- 57
- Issue
- 8
- Pages
- 2028-2036
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2494670
- OpenAlex
- W2106934282
- Cited by
- 145
- References
- 48
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 12 · 2014: 6 · 2013: 6 · 2012: 9
- FWCI
- 10.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- Sanofi
- European Foundation for the Study of Diabetes
- Ministero della Salute
- Fondation Bettencourt Schueller
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- cannabinoid type 1 receptor, rimonabant, endothelial nitric oxide synthase, mitochondrial biogenesis, white adipocytes, white adipose tissue, high-fat diet, adiposity, obesity, nitric oxide, mitochondrial DNA
- MeSH terms
- Rimonabant, Adenosine Triphosphate, Animals, Cells, Cultured, Citrate (si)-Synthase, DNA, Mitochondrial, Dose-Response Relationship, Drug, Flow Cytometry, Male, Mice, Inbred C57BL, Mitochondria, Multienzyme Complexes, Phosphorylation, Piperidines, Pyrazoles, Immunoblotting, Protein Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Receptor, Cannabinoid, CB1, Mice, Nitric Oxide Synthase Type III, Adipocytes, White, AMP-Activated Protein Kinases
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