A High Omega-6 PUFA Diet Impairs Hepatocyte Insulin Signalling During Diet-Induced Obesity

      Increased incidences of type 2 diabetes in Canada could be due to changing environmental factors like diet. Although the effects of saturated fats are well-known, the effects of omega-6 polyunsaturated fatty acids (PUFA), a major dietary fatty acid on hepatocyte insulin signalling have not been fully established. Mice were fed isocaloric, high-fat diets (40% energy from fats) rich in omega-6 PUFA (from corn oil; CO) or monounsaturated fatty acids (MUFA) (from olive oil; OO). After 5 weeks, CO induced whole body insulin resistance as measured by insulin and glucose tolerance tests. In the liver, CO but not OO decreased total liver insulin receptor substrate 1 (IRS-1) and the proportion of Ser307 phosphorylated IRS-1, signifying loss of insulin sensitivity. Differences in IRS-2 or phosphorylation on Ser318 and Ser612 of IRS-1 were not observed. Regarding P13 kinase activity, CO increased protein expression of total inhibitory p85 subunit, without affecting the expression of the catalytic p110α subunit. Phosphorylation of Tyr458, which removes the inhibition of p85 was also reduced. Total Akt and specific phosphorylations responsible for increasing insulin sensitivity were also reduced by PUFA. Overall, these results show a strong correlation between omega-6 PUFA and decreased insulin signalling, whereas MUFA was associated with increased insulin sensitivity. These results could provide important clues to elucidate the molecular basis for the rise in insulin resistance and development of type 2 diabetes in response to a high fat, omega-6 PUFA rich diet as observed among North Americans, including Canadians.
      Supported by the Canadian Diabetes Association.