Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes
- Laura Tedesco12,
- Alessandra Valerio13,
- Cristina Cervino4,
- Annalisa Cardile1,
- Claudio Pagano5,
- Roberto Vettor5,
- Renato Pasquali4,
- Michele O. Carruba12,
- Giovanni Marsicano6,
- Beat Lutz7,
- Uberto Pagotto4 and
- Enzo Nisoli12
- 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, 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 Institut National de la Santé et de la Recherche Médicale, Group AVENIR, Institute François Magendie, University Bordeaux 2, Bordeaux, France
- 7Department of Physiological Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany
- Corresponding author Enzo Nisoli, enzo.nisoli{at}unimi.it
Abstract
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.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 13 May 2008.
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U.P. has been a consultant for, has served on an advisory board for, and has received honoraria from sanofi-aventis. R.P. has received honoraria from sanofi-aventis.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted May 7, 2008.
- Received November 16, 2007.
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