Metabolic Effects of Omega-3 Long-Chain Polyunsaturated Fatty Acids

Abstract

Obesity and its associated cardiometabolic disorders are among the world’s greatest health problems. However, non-surgical weight-loss treatments are ineffective. Treatments that can reduce cardiometabolic risk in the overweight and obese are urgently needed. Further, as the offspring of obese and/or diabetic women are programmed to become obese and insulin resistant with age, interventions in pregnancy could have substantial long-term impacts on public health. Supplemental omega-3 fatty acids appear promising as they modulate important metabolic pathways and are insulin-sensitising in rats. The central hypothesis in this thesis is that long chain omega-3 polyunsaturated fatty acids, can modify the effects of gene-environment interactions to improve aspects of glucose and lipid metabolism. Four predictions were tested 1) that an n-3 PUFA supplement would be insulin sensitising in overweight men and 2) that an n-3 PUFA supplement used in a model of insulin resistant pregnancy would have metabolic benefits to the offspring 3) that fish oils sold at retail would have excessive oxidation, and 4) that an oxidised fish oil supplement would not have benefits to the offspring when used during pregnancy. I used a randomised controlled crossover trial to investigate the metabolic effects of krill/salmon blended oil on insulin sensitivity in overweight men. At baseline, higher n-3 PUFA levels were associated with greater insulin sensitivity. However, supplementation with the marine oil led to reduced insulin sensitivity, suggesting increased cardiometabolic risk. In an animal model of insulin-resistant pregnancy (maternal high-fat diet supplementation with unoxidized fish oil prevented the development of insulin resistance in the adult offspring. I found that fish oil products purchased at retail were substantially oxidised and did not meet labelled n-3 PUFA content. I then assessed the effects of oxidised fish oil supplementation during rat pregnancy, and found a substantial increase in neonatal mortality and persistent maternal insulin resistance. I have shown that oxidation changes the metabolic effects of n-3 PUFA rich supplements. It is possible that there are negative consequences to consuming oxidised fish oil during human pregnancy, and unrecognised oxidation may have confounded the n-3 PUFA clinical trial literature. Whether n-3 PUFAs have insulin-sensitising effects in humans remains unresolved.