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.
Highlights
It has been well established that the endocannabinoid system consisting of cannibinoid-1 receptor (CB1R) and CB2R and their endogenous ligands play a significant role in regulating multiple metabolic pathways [1,2,3]
We demonstrated that CB1R ASO treatment improved glycemic control and reversed hepatic steatosis
An increase in energy expenditure and improvement in lipid metabolism and glucose homeostasis may have occurred in peripheral tissues
Summary
It has been well established that the endocannabinoid system consisting of CB1R and CB2R and their endogenous ligands (anandamide and 2-arachidonoylglycerol) play a significant role in regulating multiple metabolic pathways [1,2,3]. In recent years, emerging evidence has supported the notion that blockade of CB1 receptors with antagonists in peripheral tissues may provide sufficient metabolic benefits in feeding through gut-brain signaling [20,21,22], adipose tissue metabolism [23,24], hepatic lipogenesis [23], glucose homeostasis, insulin release in the pancreas [8,25,26], cholesterol metabolism in macrophages [27] and metabolic control in skeletal muscle [28]. Targeting CB1 receptors in peripheral tissues has emerged to be a promising therapeutic approach to treat obesity, diabetes and the metabolic syndrome (for review, see [31]). We utilized the anti-sense oligonucleotide approach to evaluate the metabolic effects upon blockade of peripheral CB1R in diet-induced obesity AKR/J mouse model
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