Mixed results have been obtained regarding the level of insulin resistance induced by high-fat diets rich
in saturated fatty acids (SFA) when compared to those enriched by polyunsaturated fatty acids (PUFA),
and how metabolic effects of marine PUFA of n-3 series, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic
acid (EPA), depend on dietary lipid background. Here we compared two high-fat diets, in
which the major lipid constituent was based either on SFA in the form of pork lard (LHF diet) or PUFA of
n-6 series (Omega-6) as corn oil (cHF diet). Both cHF and LHF parental diets were also supplemented
with EPAþDHA (~30 g/kg diet) to produce cHFþF and LHFþF diet, respectively. Male C57BL/6N mice were
fed the experimental diets for 8 weeks. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic
clamps in mice fed LHF and cHF diets, and then metabolic effects of cHFþF and LHFþF diets were
assessed focusing on the liver and epididymal white adipose tissue (eWAT). Both LHF and cHF induced
comparable weight gain and the level of insulin resistance, however LHF-fed mice showed increased
hepatic steatosis associated with elevated activity of stearoyl-CoA desaturase-1 (SCD1), and lower plasma
triacylglycerol levels when compared to cHF. Despite lowering hepatic SCD1 activity, which was
concomitant with reduced hepatic steatosis reaching the level observed in cHFþF mice, LHFþF did not
decrease adiposity and the weight of eWAT, and rather further impaired insulin sensitivity relative to
cHFþF, that tended to improve it. In conclusion, high-fat diets containing as much as ~35 weight% as
lipids induce similar weight gain and impairment of insulin sensitivity irrespective whether they are
based on SFA or Omega-6. Although the SFA-rich diet containing EPAþDHA efficiently reduced hepatic
steatosis, it did so without a corresponding improvement in insulin sensitivity and in the absence of
effect on adiposity