Abstract
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.
Highlights
Obesity has reached pandemic levels taking a significant toll on the health of adults and children
We have previously demonstrated that 12/15LO knockout (KO) mice are protected from insulin resistance and adipose tissue inflammation induced by a short-term feeding with v6-enriched high fat (HF) diet [15]
This study is the first to show that reducing dietary v6/v3 fatty acid ratio, without any other diet composition changes, is sufficient to protect WT mice from long-term HF diet-induced steatohepatitis and to reduce plasma concentration of oxidized metabolites of arachidonic acid
Summary
Obesity has reached pandemic levels taking a significant toll on the health of adults and children. Obesity is associated with a range of metabolic maladies, including insulin resistance, dyslipidemia, nonalcoholic fatty liver disease (NAFLD) and hypertension, collectively grouped into the so-called metabolic syndrome [1,2,3]. The obesity-associated low-grade chronic inflammatory state in metabolic tissues, including adipose, liver, and muscle, contributes to insulin resistance and metabolic dysfunction that results from nutrient excess [4]. Corresponding to Western diets, standard high fat (HF) diet chows in rodent diet-induced obesity models are typically enriched for saturated fatty acids and polyunsaturated v6 fatty acids. Diets enriched with v3 have been shown to reduce hypertriglyceridemia [11], fatty liver disease [12,13], and improve renal function in type 2 diabetics [14]
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