| Autor: |
Iyer MS; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Paszkiewicz RL; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Bergman RN; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Richey JM; Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California., Woolcott OO; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Asare-Bediako I; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Wu Q; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Kim SP; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Stefanovski D; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Kolka CM; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Clegg DJ; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California., Kabir M; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California. |
| Abstrakt: |
CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors ( NPRs ), β-1 and β-3 adrenergic receptor ( β1R , β3R ) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1 ; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2 , the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs , β-1R and β-3R , lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM. |
