Metabolic syndrome, also known as syndrome X and insulin resistance syndrome, is a global pandemic that has been exponentially increasing throughout the last two decades. Obesity and insulin resistance are the primary components of metabolic syndrome. Our study aimed to identify factors regulating insulin resistance by further increasing our knowledge of 12/15 lipoxygenase along with a implementing a dietary intervention to reduce insulin resistance. We tested the hypothesis that 12/15 lipoxygenase transgenic mice on a 45% HFD after 10 weeks would have significantly greater insulin resistance than the wildtype mice. We also hypothesized that a dietary intervention with low glycemic index bread products along with omega-3 and polyphenol supplements for 12 weeks should decrease insulin resistance and lower the risk of developing chronic diseases more effectively than a placebo-controlled diet. The 12/15-lipoxygenase mice study showed that the 12/15 lipoxygenase transgenic mice had significantly higher fasting plasma glucose concentrations, fasting insulin concentrations, plasma triglyceride concentration, and greater gWAT percentage of body weight compared to the wildtype mice. The study also suggested that the 12/15- lipoxygenase mice had greater systemic insulin resistance than the wildtype mice. The dietary intervention study, although incomplete at this stage, showed trends for enhanced insulin sensitivity with the active diet, body weight loss, fat mass loss, waist circumference decrease and improvements in lipid panel were significant in both diet groups. These studies shed new light on mechanisms regulating insulin resistance

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.