title: Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways.
abstract: OBJECTIVE
  Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice.
  
  
  METHODS
  The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS(-/-) and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA.
  
  
  RESULTS
  ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS(-/-) mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD.
  
  
  CONCLUSIONS
  CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mice.
authors.affiliation: Integrated Laboratories Network, Center for Study and Research on Obesity, and Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tedesco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Valerio
authors.forename: Marta
authors.initials: M
authors.lastname: Dossena
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cardile
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ragni
authors.forename: Claudio
authors.initials: C
authors.lastname: Pagano
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.forename: Michele O
authors.initials: MO
authors.lastname: Carruba
authors.forename: Roberto
authors.initials: R
authors.lastname: Vettor
authors.forename: Enzo
authors.initials: E
authors.lastname: Nisoli
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D034741:RNA, Small Interfering; D043882:Receptors, Cannabinoid; C119325:arachidonyl-2-chloroethylamide; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase