Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways.
Rimonabant has been shown to not only decrease the food intake and body weight but also to increase serum adiponectin levels. This increase of the serum adiponectin levels has been hypothesized to be related to the rimonabant-induced amelioration of insulin resistance linked to obesity, although experimental evidence to support this hypothesis is lacking. To test this hypothesis experimentally, we generated adiponectin knock-out (adipo(-/-))ob/ob mice. After 21 days of 30 mg/kg rimonabant, the body weight and food intake decreased to similar degrees in the ob/ob and adipo(-/-)ob/ob mice. Significant improvement of insulin resistance was observed in the ob/ob mice following rimonabant treatment, associated with significant up-regulation of the plasma adiponectin levels, in particular, of high molecular weight adiponectin. Amelioration of insulin resistance in the ob/ob mice was attributed to the decrease of glucose production and activation of AMP-activated protein kinase (AMPK) in the liver induced by rimonabant but not to increased glucose uptake by the skeletal muscle. Interestingly, the rimonabant-treated adipo(-/-)ob/ob mice also exhibited significant amelioration of insulin resistance, although the degree of improvement was significantly lower as compared with that in the ob/ob mice. The effects of rimonabant on the liver metabolism, namely decrease of glucose production and activation of AMPK, were also less pronounced in the adipo(-/-)ob/ob mice. Thus, it was concluded that rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways.
Watanabe
Taku
T
Department of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo, Japan.
Kubota
Naoto
N
Ohsugi
Mitsuru
M
Kubota
Tetsuya
T
Takamoto
Iseki
I
Iwabu
Masato
M
Awazawa
Motoharu
M
Katsuyama
Hisayuki
H
Hasegawa
Chiaki
C
Tokuyama
Kumpei
K
Moroi
Masao
M
Sugi
Kaoru
K
Yamauchi
Toshimasa
T
Noda
Tetsuo
T
Nagai
Ryozo
R
Terauchi
Yasuo
Y
Tobe
Kazuyuki
K
Ueki
Kohjiro
K
Kadowaki
Takashi
T
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D000077285:Rimonabant
D052242:Adiponectin; C499919:Adipoq protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077285:Rimonabant