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Abstract

Dietary intake of linoleic acid (LNA, 18:2n-6) has increased dramatically during the 20th century and is associated with greater prevalence of obesity. The endocannabinoid system is involved in regulation of energy balance and a sustained hyperactivity of the endocannabinoid system may contribute to obesity. Arachidonic acid (ARA, 20:4n-6) is the precursor for 2-AG and anandamide (AEA), and we sought to determine if low fat diets (LFD) could be made obesogenic by increasing the endocannabinoid precursor pool of ARA, causing excessive endocannabinoid signaling leading to weight gain and a metabolic profile associated with obesity. Mice (C57BL/6j, 6 weeks of age) were fed 1 en% LNA and 8 en% LNA in low fat (12.5 en%) and medium fat diets (MFD, 35 en%) for 16 weeks. We found that increasing dietary LNA from 1 to 8 en% in LFD and MFD significantly increased ARA in phospholipids (ARA–PL), elevated 2-AG and AEA in liver, elevated plasma leptin, and resulted in larger adipocytes and more macrophage infiltration in adipose tissue. In LFD, dietary LNA of 8 en% increased feed efficiency and caused greater weight gain than in an isocaloric reduction to 1 en% LNA. Increasing dietary LNA from 1 to 8 en% elevates liver endocannabinoid levels and increases the risk of developing obesity. Thus a high dietary content of LNA (8 en%) increases the adipogenic properties of a low fat diet.

Animals

Male mice (n = 36), 6 weeks of age (C57BL/6j, Taconic, Denmark) were randomly assigned to four experimental diets (n = 9) (Table ) and housed individually. The animals were maintained on a 12:12 h light–dark cycle at 29 ± 1 °C. All animals were sacrificed at 22 weeks of age. Table 1Diet composition and fatty acid profile of dietsLow fat diets (12.5 en%)Medium fat diets (35 en%)1 en% LNA8 en% LNA1 en% LNA8 en% LNAg/kg Cocosa (coconut oil)3–12985 Safflower oil144–42 Olive oil44–3331 Flaxseed oil2637 Total oil added (g/kg)5050165165% energy derived from Fat11113234 Carbohydrate71714544 Protein18182322(% of energy) Sum SFA2.51.52517 Sum MUFA9278 18:2n-61818 20:4n-6–––– Sum n-61818 18:3n-30.30.90.41 20:5n-3–––– 22:6n-3–––– Sum n-30.30.90.31 Total n-6/n-3 ratio3938 Estimated n-6 HUFA1 (%)56725372 Estimated Omega-3 Index2 11511.55.5All diets were supplemented with 60 mg/k ethoxyquin, 2.5 g/kg choline bitartrate, 3 g/kg l-cystein, 13 g/kg vitamin mix, 47 g/kg mineral mix, 50 g/kg sucrose, 50 g/kg cellulose, 100 g/kg corn starch. Energy (kcal) of diets; LF diets; 3,900, MF diets; 4,500 LNA linoleic acid, SFA saturated fatty acids, MUFA monounsaturated fatty acids, HUFA highly unsaturated fatty acids (>20 carbon) 1 Calculated from the Lands equation [], n-3 HUFA = 100 − n-6 HUFA 2 Omega-3 index: (omega-3 HUFA × 0.32) − 3.5 [, ]