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Abstract
Background:Cannabinoid type-1 (CB1) receptor inverse agonists improve type 2 diabetes and dyslipidaemia but were discontinued due to adverse psychiatric effects. Δ9-Tetrahydrocannabivarin (THCV) is a neutral CB1 antagonist producing hypophagia and body weight reduction in lean mice. We investigated its effects in dietary-induced (DIO) and genetically (ob/ob) obese mice.Methods:We performed two dose-ranging studies in DIO mice; study 1: 0.3, 1, 2.5, 5 and 12.5 mg kg−1, oral twice daily for 30 days and study 2: 0.1, 0.5, 2.5 and 12.5 mg kg−1, oral, once daily for 45 days. One pilot (study 3: 0.3 and 3 mg kg−1, oral, once daily) and one full dose-ranging (study 4: 0.1, 0.5, 2.5 and 12.5 mg kg−1, oral, once daily) studies in ob/ob mice for 30 days. The CB1 inverse agonist, AM251, oral, 10 mg kg−1 once daily or 5 mg kg−1 twice daily was used as the positive control. Cumulative food and water intake, body weight gain, energy expenditure, glucose and insulin levels (fasting or during oral glucose tolerance tests), plasma high-density lipoprotein and total cholesterol, and liver triglycerides were measured. HL-5 hepatocytes or C2C12 myotubes made insulin-resistant with chronic insulin or palmitic acid were treated with 0, 1, 3 and 10 μℳ THCV or AM251.Results:THCV did not significantly affect food intake or body weight gain in any of the studies, but produced an early and transient increase in energy expenditure. It dose-dependently reduced glucose intolerance in ob/ob mice and improved glucose tolerance and increased insulin sensitivity in DIO mice, without consistently affecting plasma lipids. THCV also restored insulin signalling in insulin-resistant hepatocytes and myotubes.Conclusions:THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.
Highlights
The clinical evidence for the efficacy of inverse agonists of the cannabinoid type-1 (CB1) receptor for the improvement of the metabolic status of animals with metabolic syndrome, type 2 diabetes and dyslipidaemia has grown over the past decade and is widely recognized
To induce myotube formation, cells were grown to 90% confluence in six-well plates and switched to differentiation media DMEM supplemented with 1% FBS, penicillin/streptomycin and amphotericin B (Sigma, St Louis, MO, USA) for 3 days before treatment with 250 mM palmitic acid for only 24 h, in the absence or presence of THCV or AM251 at the indicated concentrations before being switched to serum-free media containing 250 mM palmitic acid, with or without THCV or AM251 for 2 h followed by stimulation with 100 nM insulin for 15 min
Study 1 and study 2 Effect of THCV on body weight in dietary-induced obese (DIO) mice: In study 1 in DIO mice, AM251 (5 mg kg À 1 twice daily), a synthetic inverse agonist at Cannabinoid type-1 (CB1) receptors used as a positive control, reduced body weight by a mean of 48 g (Po0.001), whereas THCV at doses from 0.3 to 12.5 mg kg À 1 twice daily had no significant effect on body weight (Figure 1a)
Summary
Cannabinoid type-1 (CB1) receptor inverse agonists improve type 2 diabetes and dyslipidaemia but were discontinued due to adverse psychiatric effects. METHODS: We performed two dose-ranging studies in DIO mice; study 1: 0.3, 1, 2.5, 5 and 12.5 mg kg À 1, oral twice daily for 30 days and study 2: 0.1, 0.5, 2.5 and 12.5 mg kg À 1, oral, once daily for 45 days. RESULTS: THCV did not significantly affect food intake or body weight gain in any of the studies, but produced an early and transient increase in energy expenditure. It dose-dependently reduced glucose intolerance in ob/ob mice and improved glucose tolerance and increased insulin sensitivity in DIO mice, without consistently affecting plasma lipids.
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