Rational Design of a Functional Fatty Acid Component for Alleviating Western Diet-Induced Insulin Resistance and Glycolipid Metabolism Disorders

This research aimed to systematically investigate the regulatory effects of six key fatty acids and rationally designed a functional fatty acid component (FFAC) to alleviate palmitic acid (PA)-induced glycolipid metabolism disorders and insulin resistance (IR) in HepG2 cells and Western diet-induced IR in the C57BL/6 mice model. In vitro experiments showed that saturated fatty acids such as PA and stearic acid (SA) induced concentration-dependent cytotoxicity and IR in HepG2 cells, while unsaturated fatty acids, including palmitoleic acid (POA), oleic acid (OA), linoleic acid (LA), and α-linolenic acid (ALA), enhanced cell viability and exerted protective effects. Based on the principle of balanced fatty acid ratio and the obtained cell experimental results, FFAC was designed as PA:SA:POA:OA:LA:ALA = 4:1:1:4:4:1 and formulated using dietary oils. In vivo, a 13-week dietary intervention revealed that FFAC substitution mitigated Western diet-induced weight gain, systemic IR, serum lipid disorders, and hepatic steatosis in mice. Mechanistically, FFAC restored the IRS1/PI3K/Akt/GSK3β insulin signaling pathway in HepG2 cells and reshaped gut microbiota by enriching beneficial genera such as <i>Akkermansia</i>. These findings demonstrated that FFAC effectively alleviates diet-induced metabolic disorders through multiple pathways, highlighting the potential of rationally designed dietary fatty acid compositions in managing metabolic disorders.