CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors
| Autor: | Viorica Ionut, Stella P. Kim, Darko Stefanovski, Morvarid Kabir, Malini S. Iyer, Karyn J. Catalano, Isaac Asare Bediako, Cathryn M. Kolka, Jenny D. Chiu, Orison O. Woolcott, Joyce M. Richey, Isabel R. Hsu, Qiang Wu, Richard N. Bergman |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Physiology Metabolic Clearance Rate Endocrinology Diabetes and Metabolism medicine.medical_treatment Biology Diet High-Fat Insulysin Insulin resistance Dogs Rimonabant Lipid oxidation Downregulation and upregulation Piperidines Receptor Cannabinoid CB1 Antigens CD Physiology (medical) Internal medicine medicine Animals Insulin RNA Messenger Receptor Cannabinoid Receptor Antagonists Adiponectin digestive oral and skin physiology nutritional and metabolic diseases Articles Glucose clamp technique medicine.disease Up-Regulation Endocrinology Liver Glucose Clamp Technique Pyrazoles Insulin Resistance Receptors Adiponectin Cell Adhesion Molecules hormones hormone substitutes and hormone antagonists medicine.drug |
| Popis: | The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFD+RIM; n = 11) or placebo (HFD+PL; n = 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic-hyperinsulinemic clamp. The HFD+PL group showed a decrease in MCR; in contrast, the HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway. |
| Databáze: | OpenAIRE |
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