Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.
OBJECTIVE
Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.


METHODS
Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.


RESULTS
Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake.


CONCLUSIONS
Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight.
Nogueiras
Ruben
R
Department of Psychiatry, Obesity Research Centre, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio, USA. ruben.nogueiras@usc.es
Veyrat-Durebex
Christelle
C
Suchanek
Paula M
PM
Klein
Marcella
M
Tschöp
Johannes
J
Caldwell
Charles
C
Woods
Stephen C
SC
Wittmann
Gabor
G
Watanabe
Masahiko
M
Liposits
Zsolt
Z
Fekete
Csaba
C
Reizes
Ofer
O
Rohner-Jeanrenaud
Francoise
F
Tschöp
Matthias H
MH
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002853:Chromatography, Liquid; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D015309:Glucose Clamp Technique; D050356:Lipid Metabolism / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014280:Triglycerides; D064429:Fatty Acid Synthases; D008071:Lipoprotein Lipase; D000103:Acetyl-CoA Carboxylase; D000077285:Rimonabant