Biosynthesis of long-chain n-3 fatty acids from precursors is limited. In vivo effect of squalene (SQ) on the metabolic fate of n-3 fatty acid precursors in obese/diabetic KK-A(y) rodent model was evaluated in our work. Soybean oil, being rich in ALA (18:3 n-3; a known precursor of EPA/DHA), was chosen as the n-3 fatty acid precursor rich source. A high-fat diet (20%) containing 7% soybean oil (SO) was fed to obesity/diabetes-prone male KK-A(y) mice (control). In the case of diets fed to test groups, soybean oil was replaced with 5% SO and 2% SQ. Hepatic DHA levels increased (four fold) in SQ fed group over control (p<0.05). Gene and protein expressions of (5) and (6) desaturases, key enzymes involved in the fatty acid metabolism, further supported the results. Also, SQ exhibited a hypotriglyceridemic and hypoglycemic effect. The results clearly indicated the effect of SQ in modulating the n-3 fatty acid metabolism, including EPA/DHA synthesis in the presence of n-3 fatty acid precursor. This is the first report of enhancement of in vivo DHA/EPA by SQ and in turn, modulating the physiological fatty acid profile. Practical applications: Squalene (SQ) is an important marine biofunctional material that is found in some terrestrial sources as well. Squalene, being a cholesterol precursor, forms an interesting subject of research for its effect in vivo. SQ significantly enhanced proportions of EPA and/or DHA when their n-3 fatty acid precursors were available in the diet. The study further establishes the usefulness of SQ in functional food formulations. The work provides an important basis for further evaluation of the role of SQ in normal and disease conditions.KK-A(y) mice were fed high fat/sucrose diet to induce obesity/diabetes. Fat source in control diet was lard and soybean oil while experimental group diet contained 2% squalene+13% lard+5% soybean oil. Feeding squalene for 4weeks modulated fatty acid metabolism with increased docosahexaenoic acid (DHA) and decrease in triglycerides (TG), compared to control. The enhanced DHA in the fatty acid profile was supported by upregulated mRNA expression of (5)-desaturase enzyme and protein expression of (5) and (6) desaturases (FADS1 and FADS2). Additionally, squalene had a hypoglycemic effect in the mice
