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Beneficial metabolic effects of CB1R anti-sense oligonucleotide treatment in diet-induced obese AKR/J mice
Yuting Tang1, George Ho, Yaxin Li
1Cardiovascular and Metabolism Therapeutic Area, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States of America. ytang69@yahoo.com
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 (46.1±1.0 g vs veh, 51.2±0.9 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, 145±4 mg/dL vs veh, 195±10 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. SREBP1 mRNA expression was decreased in both epididymal fat and liver. G6PC and fatty acid translocase/CD36 mRNA levels were also reduced in the liver. In summary, CB1R ASO treatment in DIO AKR/J mice led to improved insulin sensitivity and glucose homeostasis. The beneficial effects of CB1R ASO treatment strongly support the notion that selective inhibition of the peripheral CB1R, without blockade of central CB1R, may serve as an effective approach for treating type II diabetes, obesity and the metabolic syndrome.
Insights
Peripheral cannabinoid-1 receptor (CB1R) blockade using an anti-sense oligonucleotide (ASO) in diet-induced obese mice improved metabolic health. This approach effectively reduced body weight, fat mass, and improved glucose homeostasis, suggesting potential for treating type II diabetes and obesity.
Area of Science:
- Metabolic research
- Pharmacology
- Obesity and diabetes research
Background:
- Cannabinoid-1 receptor (CB1R) plays significant roles in peripheral metabolic regulation.
- Understanding the impact of peripheral CB1R blockade is crucial for metabolic disease treatment.
Purpose of the Study:
- To investigate the metabolic effects of selectively blocking peripheral CB1R function using an anti-sense oligonucleotide (ASO) in diet-induced obese (DIO) mice.
- To evaluate the therapeutic potential of peripheral CB1R inhibition for metabolic disorders.
Main Methods:
- A 10-week study involving DIO AKR/J mice treated with varying doses of CB1R ASO (Isis-414930) or a control ASO.
- Measurements included CB1R mRNA levels, body weight, body fat mass, fed glucose levels, oral glucose tolerance tests, liver steatosis, and plasma biomarkers.
Main Results:
- CB1R ASO significantly reduced CB1R mRNA in epididymal fat and kidney.
- Dose-dependent reductions in body weight gain and body fat mass were observed.
- Improved glucose tolerance, decreased fed glucose levels, reduced liver steatosis, and lower plasma insulin and leptin were noted.
- Downregulation of SREBP1, G6PC, and CD36 mRNA in liver and fat tissues.
Conclusions:
- Selective peripheral CB1R inhibition via ASO treatment improved insulin sensitivity and glucose homeostasis in DIO mice.
- This targeted approach offers a promising strategy for managing obesity, type II diabetes, and metabolic syndrome without central nervous system effects.
