Obesity is associated with metabolic perturbations including liver and adipose tissue
inflammation,
insulin resistance, and
type 2 diabetes.
Omega-6 fatty acids (ω6) promote and
omega-3 fatty acids (ω3) reduce
inflammation as they can be metabolized to pro- and anti-inflammatory
eicosanoids, respectively. 12/
15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue
inflammation and
insulin resistance. We examined how these conditions affect circulating concentrations of oxidized metabolites of ω6 arachidonic and
linoleic acids and innate and adaptive immune system activity in the liver. For 15 weeks, wild-type (WT) mice were fed either a
soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11∶1, HFH), similar to Western-style diet, or a fat Kcal-matched,
fish oil-enriched HF diet with a low dietary ω6/ω3 ratio of 2.7∶1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published
fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL were protected from HFH-diet induced
steatohepatitis, evidenced by decreased hepatic
mRNA expression of pro-inflammatory genes and genes involved in lymphocyte homing, and reduced deposition of hepatic
triglyceride. Furthermore, oxidized metabolites of ω6
arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced
fatty liver and elevated
mRNA markers of
inflammation and lymphocyte homing. 12/15-LOKO mice were protected from HFH-induced
insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate
insulin resistance or adipose tissue
inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reduces
steatohepatitis.