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Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through eNOS expression in white adipocytes

¹Integrated Laboratories Network, Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, Milan University, Milan, Italy
²Istituto Auxologico Italiano, Milan, Italy
³Department of Biomedical Sciences and Biotechnologies, Brescia University, Brescia, Italy
⁴Endocrinology Unit, Department of Internal Medicine and Gastroenterology, and Center for Applied Biomedical Research S. Orsola-Malpighi Hospital, Alma Mater Bologna University, Bologna, Italy
⁵Endocrine-Metabolic Laboratory, Internal Medicine, Department of Medical and Surgical Sciences, Padua University, Padua, Italy
⁶U862 INSERM, Group AVENIR, Institute François Magendie, University Bordeaux 2, Bordeaux, France
⁷Department of Physiological Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany

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 the hypothesis 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 standard (STD) or high-fat diet (HFD).

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 HFD-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 STD, 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 HFD-induced fat accumulation, without concomitant changes in food intake.

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