Selective cannabinoid - 1 receptor blockade significantly benefits fatty acid and triglyceride 1 metabolism in weight - stable nonhuman primates 2

34 The goal of this study was to determine whether administration of the CB1-cannabinoid receptor 35 antagonist, rimonabant, would alter fatty acid flux in non-human primates. Five adult baboons (Papio 36 Sp), aged 12.1 ± 4.7y (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty 37 acid and TG flux before and after 7 wks of treatment with rimonabant (15 mg/d). Animals were fed ad 38 libitum diets and stable isotopes were administered via diet (d31-tripalmitin) and intravenously (C439 palmitate, C1-acetate). Plasma was collected in the fed and fasted states and blood lipids analyzed by 40 GC/MS. DEXA was used to assess body composition and a hyperinsulinemic-euglycemic clamp used to 41 assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, 42 body weight, plasma and tissue endocannabinoid concentrations, or the quantity of liver-TG fatty acids 43 originating from de novo lipogenesis (19 ± 6% vs 16 ± 5%, for preand post-treatment respectively, 44 P=0.39). However, waist circumference was significantly reduced 4% in the treated animals (P<0.04), 45 glucose disposal increased 30% (P=0.03), and FFA turnover increased 37% (P=0.02). The faster FFA 46 flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3% vs 23 47 ± 4%, P=0.02) and 2-fold increase in TRL-TG turnover (1.5 ± 0.9 vs 3.1 ± 1.4 μmol/kg/h, P=0.03). 48 These data support the potential for a strong effect of CB1 receptor antagonism at the level of adipose 49 tissue resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose 50 storage, and significant improvements in glucose homeostasis. 51 52