Dietary Linoleic Acid Elevates Endogenous Endocannabinoids (2‐AG and Anandamide) and Induces Obesity

Abstract

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The endocannabinoids 2‐arachidonoylglycerol (2‐AG) and anandamide (AEA) derive from arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated to reflect dietary increases in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium‐fat diets (35 en% fat) and high‐fat diets (60 en%) for 14 weeks from weaning.ResultsIncreasing LA from 1 en% to 8 en% elevated AA‐phospholipids (PL) in liver and erythrocytes, tripled 2‐AG + 1‐AG and AEA associated with increased food intake, feed efficiency, and adiposity. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. In summary, increasing prevalence rates of obesity 20th century were successfully modeled; elevating dietary LA increased tissue AA and induced hyperactive endocannabinoid status, subsequently resulting in obesity.