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

Abstract

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) is the omega-6 fatty acid 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. Linoleic acid was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the US 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. Increasing LA from 1 en% to 8 en% elevated AA -phospholipids in liver and erythrocytes, tripled 2-AG+1-AG and AEA associated with increased food intake, feed efficiency and adiposity in mice. Reducing AA - phospholipids by adding 1en% long-chain omega-3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2-AG+1-AG and AEA resulting in the development of diet-induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA –phospholipid pool and normalize endocannabinoid tone.

Dietary n-6 PUFA, carbohydrate:protein ratio and change in body weight and waist circumference: a follow-up study

“…Still, in man, the effect of n-6 PUFA on obesity development has not been investigated in detail. The findings from the mouse experiment by Alvheim et al (2) are in line with other animal experiments which …”

“…Generally, animal experiments used high doses of n-6 PUFA (5)(6)(7)(8) , such as 22 % of energy from n-6 PUFA in the mouse experiment by Madsen et al (9) (Lise Madsen, personal communication, 2013), but did not provide information on lower intakes compatible with intakes in the general population. However, in the mouse experiment by Alvheim et al (2) increasing 18 : 2n-6 from 1 % to 8 % of energy in the feed was sufficient to promote obesity. In the mouse experiment by Madsen et al (9) , the intake of carbohydrates constituted 8 % of the energy intake in the low-carbohydrate group and 37 % in the high-carbohydrate group; intakes below the 10th percentile intake in the present study.…”

“…Studies on the evolutionary aspects of diet indicate that major changes have taken place in the Western diet, particularly during the last 100 years; changes that correlate with the increasing prevalence of obesity (2) . Today, more than 85 % of the total intake of n-6 and n-3 PUFA is n-6 PUFA (3) .…”

Modulation of plasma N-acylethanolamine levels and physiological parameters by dietary fatty acid composition in humans

“…The reactive roles of endocannabinoids and their response to energy balance are well established; however, the important impact of diet fat selection as proactive precursors to circulating endocannabinoids and their role in metabolic control are still widely unknown ( 12,13 ). Previous research has confi rmed that a linoleicrich diet elevates AEA levels, whereas a diet supplemented with n-3 PUFAs DHA and EPA reduced AEA levels along with improving metabolic profi les in obese rats ( 14,15 ). For instance, one study indicated that consumption of krill oil (2 g/day) over 4 weeks signifi cantly reduced plasma 2-AG levels and was directly correlated to the plasma n-6/n-3 ratio in obese subjects ( 15 ).…”

Early Low-Fat Diet Enriched With Linolenic Acid Reduces Liver Endocannabinoid Tone and Improves Late Glycemic Control After a High-Fat Diet Challenge in Mice

“…As a consequence, a dietary supplementation in LA (11,12) or AA itself (13) is able to elevate the tissue contents of EC. Conversely, diets enriched with n-3 polyunsaturated FAs, such as eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (DHA [or C22:6n-3]), cause a decrease in 2-AG and AEA levels because of the replacement of AA in phospholipids with such FAs (13,14).…”