title: CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors.
abstract: 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.
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and morvarid.kabir@cshs.org.
authors: Morvarid
authors: M
authors: Kabir
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Malini S
authors: MS
authors: Iyer
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: Joyce M
authors: JM
authors: Richey
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Orison O
authors: OO
authors: Woolcott
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Isaac
authors: I
authors: Asare Bediako
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Qiang
authors: Q
authors: Wu
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Stella P
authors: SP
authors: Kim
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Darko
authors: D
authors: Stefanovski
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Cathryn M
authors: http://orcid.org/0000-0002-6636-7062
authors: CM
authors: Kolka
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: Isabel R
authors: IR
authors: Hsu
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: Karyn J
authors: KJ
authors: Catalano
authors: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: Jenny D
authors: JD
authors: Chiu
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Viorica
authors: V
authors: Ionut
authors: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and.
authors: Richard N
authors: RN
authors: Bergman
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat; D004285:Dogs; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007339:Insulysin / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D054419:Receptors, Adiponectin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D063387:Cannabinoid Receptor Antagonists; D015815:Cell Adhesion Molecules; D007328:Insulin; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D054419:Receptors, Adiponectin; D007339:Insulysin; D000077285:Rimonabant
keywords: CB1R antagonist; dogs; insulin clearance; insulin resistance; liver