Alpha-Linolenic acid-enriched butter attenuated high fat diet-induced insulin resistance and inflammation by promoting bioconversion of n-3 PUFA and subsequent oxylipin formation

Authors: FAN, RONG - University Of Nebraska; KIM, JUDY - University Of Nebraska; YOU, MIKYOUNG - University Of Nebraska; GIRAUD, DAVID - University Of Nebraska; TONEY, ASHLEY - University Of Nebraska; SHIN, SEUNG-HO - Sunseo Omega3; KIM, SO-YOUN - University Of Nebraska; BORKOWSKI, KAMIL - University Of California, Davis; Newman, John; CHUNG, SOONKYU - University Of Nebraska

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/4/2019
Publication Date: 11/12/2019
Citation: Fan, R., Kim, J., You, M., Giraud, D., Toney, A.M., Shin, S., Kim, S., Borkowski, K., Newman, J.W., Chung, S. 2019. Alpha-Linolenic acid-enriched butter attenuated high fat diet-induced insulin resistance and inflammation by promoting bioconversion of n-3 PUFA and subsequent oxylipin formation. Journal of Nutritional Biochemistry. 76. https://doi.org/10.1016/j.jnutbio.2019.108285.
DOI: https://doi.org/10.1016/j.jnutbio.2019.108285

Interpretive Summary: Increasing omega 3 (n3) polyunsaturated fatty acids (PUFAs) in the habitual diet may have benefits to metabolic health. Alpha-linolenic acid (ALA) is an eighteen carbon n3 PUFA that cannot be synthesized in the human body, but is a required precursor for the production of long-chain n-3 PUFAs like eicosapentenoic acid (EPA). However, long chain n-3 PUFA biosynthesis is limited in a many Western-type diets, likely due to an overabundance of linoleic acid (LA), an eighteen carbon omega 6 (n-6) PUFA. We hypothesized that reducing the dietary n 6/n-3 PUFA ratio would promote the biosynthesis of long-chain n-3 PUFA, and attenuate high fat (HF) diet-induced obesity and inflammation. C57BL/6 mice were fed a HF diet from either ALA-enriched butter (n3Bu, n-6/n-3 =1) or isocaloric HF diets prepared with either conventional butter lacking both ALA and LA (Bu, n-6/n 3 =6), or margarine containing a similar amount of ALA and abundant LA (Ma, n-6/n-3=6). Quantitatively measuring a wide array of lipids and lipid mediators revealed that n3Bu feeding promoted the biosynthesis of long-chain n-3 PUFA and their oxygenated metabolites (oxylipins) derived from ALA and EPA. The n3Bu supplementation reduced hepatic triglyceride accumulation and adipose tissue inflammation, and improved insulin sensitivity. The n3Bu-dependent decrease in inflammation was attributed to the suppressed activation of the inflammatory cytokine NFkB and a downregulation of M1 macrophage polarization. Collectively, our work suggests that dietary reduction of the n-6/n-3 PUFA ratio, rather than total n-3 PUFA consumed, can facilitates n 3 PUFA biosynthesis and subsequent lipidomic modifications that confer metabolic benefits against obesity-induced inflammation and insulin resistance.

Technical Abstract: Alpha-Linolenic acid (ALA) is an essential fatty acid and the precursor for long-chain n-3 PUFA. However, biosynthesis of n-3 PUFA is limited in a Western diet likely due to an overabundance of n-6 PUFA. We hypothesized that dietary reduction of n-6/n-3 PUFA ratio is sufficient to promote the biosynthesis of long-chain n-3 PUFA, leading to an attenuation of high fat (HF) diet-induced obesity and inflammation. C57BL/6 mice were fed a HF diet from ALA-enriched butter (n3Bu, n-6/n-3 =1) in comparison with isocaloric HF diets from either conventional butter lacking both ALA and LA (Bu, n-6/n-3 =6), or margarine containing a similar amount of ALA and abundant LA (Ma, n-6/n-3=6). Targeted lipidomic analyses revealed that n3Bu feeding promoted the bioconversion of long-chain n-3 PUFA and their oxygenated metabolites (oxylipns) derived from ALA and EPA. The n3Bu supplementation attenuated hepatic TG accumulation and adipose tissue inflammation, resulting in improved insulin sensitivity. The decreased inflammation by n3Bu feeding was attributed to the suppression of NFkB activation and M1 macrophage polarization. Collectively, our work suggests that dietary reduction of the n-6/n-3 PUFA ratio, rather than total n-3 PUFA consumed, is a crucial determinant that facilitates n 3 PUFA biosynthesis and subsequent lipidomic modifications, thereby conferring metabolic benefits against obesity-induced inflammation and insulin resistance.