Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways.

Abstract

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.

• Authors: Taku Watanabe, Naoto Kubota, Mitsuru Ohsugi, Tetsuya Kubota, Iseki Takamoto, Masato Iwabu, Motoharu Awazawa, Hisayuki Katsuyama, Chiaki Hasegawa, Kumpei Tokuyama, Masao Moroi, Kaoru Sugi, Toshimasa Yamauchi, Tetsuo Noda, Ryozo Nagai, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Takashi Kadowaki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 3 Pg. 1803-12 (Jan 16 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19008231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adiponectin
• Adipoq protein, mouse
• Piperidines
• Pyrazoles
• AMP-Activated Protein Kinases
• Glucose
• Rimonabant

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adiponectin (blood, genetics)
• Animals
• Body Weight (drug effects)
• Eating (drug effects)
• Glucose (metabolism)
• Insulin Resistance (genetics)
• Liver (metabolism)
• Mice
• Mice, Knockout
• Mice, Obese
• Muscle, Skeletal (metabolism)
• Piperidines (pharmacology)
• Pyrazoles (pharmacology)
• Rimonabant