beneficial metabolic effects of cb1r anti-sense oligonucleotide treatment in diet-induced obese akrj mice有益的代谢影响cb1r反义寡核苷酸治疗食源性肥胖akrj老鼠.pdfVIP

Beneficial Metabolic Effects of CB1R Anti-Sense Oligonucleotide Treatment in Diet-Induced Obese AKR/J Mice Yuting Tang*, George Ho, Yaxin Li, Meghan A. Hall, Robert L. Hills, Shawn C. Black, Yin Liang, Keith T. Demarest Cardiovascular and Metabolism Therapeutic Area, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States of America Abstract An increasing amount of evidence supports pleiotropic metabolic roles of the cannibinoid-1 receptor (CB1R) in peripheral tissues such as adipose, liver, skeletal muscle and pancreas. To further understand the metabolic consequences of specific blockade of CB1R function in peripheral tissues, we performed a 10-week-study with an anti-sense oligonucleotide directed against the CB1R in diet-induced obese (DIO) AKR/J mice. DIO AKR/J mice were treated with CB1R ASO Isis-414930 (6.25, 12.5 and 25 mg/kg/week) or control ASO Isis-141923 (25 mg/kg/week) via intraperitoneal injection for 10 weeks. At the end of the treatment, CB1R mRNA from the 25 mg/kg/week CB1R ASO group in the epididymal fat and kidney was decreased by 81% and 63%, respectively. Body weight gain was decreased in a dose-dependent fashion, significantly different in the 25 mg/kg/week CB1R ASO group (46.161.0 g vs veh, 51.260.9 g, p,0.05). Body fat mass was reduced in parallel with attenuated body weight gain. CB1R ASO treatment led to decreased fed glucose level (at week 8, 25 mg/kg/week group, 14564 mg/dL vs veh, 195 610 mg/dL, p,0.05). Moreover, CB1R ASO treatment dose-dependently improved glucose excursion during an oral glucose tolerance test, whereas control ASO exerted no effect. Liver steatosis was also decreased upon CB1R ASO treatment. At the end of the study, plasma insulin and leptin levels were significantly reduced by 25 mg/kg/ week CB1R ASO treatment. S