Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes.
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.


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.
Tedesco
Laura
L
Integrated Laboratories Network, Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, Milan University, Milan, Italy.
Valerio
Alessandra
A
Cervino
Cristina
C
Cardile
Annalisa
A
Pagano
Claudio
C
Vettor
Roberto
R
Pasquali
Renato
R
Carruba
Michele O
MO
Marsicano
Giovanni
G
Lutz
Beat
B
Pagotto
Uberto
U
Nisoli
Enzo
E
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant
D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D010880:Piperidines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D002950:Citrate (si)-Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077285:Rimonabant