Dietary Linoleic Acid Elevates the Endocannabinoids 2‐AG and Anandamide and Promotes Weight Gain in Mice Fed a Low Fat Diet

Anita Røyneberg Alvheim,Joseph R Hibbeln,Lise Madsen,Erik‐Jan Lock,Haldis Haukås Lillefosse,Yu Hong Lin,Marian Kjellevold Malde,Livar Frøyland,Bente E Torstensen

doi:10.1007/s11745-013-3842-y

Anita Røyneberg Alvheim, Joseph R Hibbeln + Show 7 more

Open Access

https://doi.org/10.1007/s11745-013-3842-y

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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.

Highlights

The endocannabinoid signaling system includes the endogenous ligands 2-arachidonoylglycerol (2-AG) and N-Lipids (2014) 49:59–69 arachidonoylethanolamine [1,2,3,4] and the cannabinoid receptors (CB1 and CB2) [5, 6]
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
We demonstrate here for the first time that an LFD can be made obesogenic by inclusion of 8 en% LNA, subsequently stimulating excessive endocannabinoid activity in the liver and weight gain

Summary

Introduction

The endocannabinoid signaling system includes the endogenous ligands 2-arachidonoylglycerol (2-AG) and N-Lipids (2014) 49:59–69 arachidonoylethanolamine (anandamide or AEA) [1,2,3,4] and the cannabinoid receptors (CB1 and CB2) [5, 6]. Activation of the cannabinoid receptor CB1 by endocannabinoids or exogenous agonists, centrally and peripherally, favors metabolic processes that stimulate appetite, increase food intake, activates fat storage pathways and down regulates catabolism resulting in adipose accretion [7, 10]. Under normal circumstances the endocannabinoid system is only activated on demand in response to acute stimulation, but has been found to be tonically overactivated in animal models of genetic and diet-induced obesity [10,11,12,13,14,15]. Down regulation of excessive endocannabinoid system activity is being actively pursued to reduce obesity [16]. Because pharmacological blockade of the CB1 receptor is effective in treating obesity and related metabolic derangements [17, 18], a dietary approach to diminish endocannabinoid hyperactivity may represent a safer alternative than pharmaceuticals [19, 20]. We are addressing an underlying cause of endocannabinoid overactivation that can potentially be translated into a safe alternative to prevent human obesity

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