Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes.
Diabetes. 2008-05-13; 57(8): 2028-2036
DOI: 10.2337/db07-1623
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1. Diabetes. 2008 Aug;57(8):2028-36. doi: 10.2337/db07-1623. Epub 2008 May 13.
Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through
endothelial nitric oxide synthase expression in white adipocytes.
Tedesco L(1), Valerio A, Cervino C, Cardile A, Pagano C, Vettor R, Pasquali R,
Carruba MO, Marsicano G, Lutz B, Pagotto U, Nisoli E.
Author information:
(1)Integrated Laboratories Network, Center for Study and Research on Obesity,
Department of Pharmacology, Chemotherapy and Medical Toxicology, School of
Medicine, Milan University, Milan, Italy.
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.
DOI: 10.2337/db07-1623
PMCID: PMC2494670
PMID: 18477809 [Indexed for MEDLINE]