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Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity

Alvheim AR, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR (2012) Obesity (Silver Spring) 10 1984-94. doi: 10.1038/oby.2012.38. Epub 2012 Feb 15. 

Web URL: View this and related abstracts via PubMed here. Free full text of this article is available online.


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 ω-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.

LA 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 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.

Increasing 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 in mice.

Reducing AA-PL by adding 1 en% long-chain ω-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-PL pool and normalize endocannabinoid tone.


This elegant study shows that increasing the dietary intake of the main omega-6 polyunsaturated fat found in vegetable oils (linoleic acid, LA) causes obesity in mice. 

It also provides evidence that an omega-6-rich diet promotes obesity by increasing endocannabinoid substances that increase appetite.

The endocannabinoid 2-AG promotes increased appetite, and this substance is made within the body from the long-chain omega-6 fatty acid, arachidonic acid (AA). As predicted, levels of both omega-6 AA and its derivative 2-AG were significantly higher in mice fed a diet rich in omega-6 LA.

Importantly, this high omega-6 LA diet (providing 8% of energy/calories as LA) was chosen to match the current dietary intake of US humans.

Furthermore, the researchers also showed that the obesity-promoting effect of the high omega-6 LA diet was counteracted by adding the long-chain omega-3 EPA/DHA (found in fish and seafood) at just 1% of energy/calories.

These findings show that obesity can be caused by just the kinds of changes in dietary fat intake that have taken place in human diets over the 20th century - particularly in recent decades.  Modern, western-type diets - rich in highly processed foods made with vegetable seed oils - have a very high omega-6 / omega-3 ratio relative to any traditional human diet.

Specifically, this study shows that such high intakes of omega-6 fats from vegetable oils, together with low intakes of the long-chain omega-3 fats found in fish and seafood, directly promote appetite and weight gain via known biochemical mechanisms.

Rigorously controlled and detaled studies like ths one are not possible in humans for obvious reasons. 

However, the findings both match and help to explain the current obesity epidemic as a predictable result from the uncontrolled dietary experiment that has been going on in humans over the last century or more - but particularly in recent decades - in terms of the increasing industrialisation of our food supply.

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