This paper reports on the effects of fish oil and chronic exercise on chylomicron and lipid metabolism in men with insulin resistance. Subjects taking fish oil showed a reduced postprandial TAG response to the moderate fat-containing meal after four weeks. Following the 12 week walking program the fish oil group exhibited an even greater postprandial TAG reduction, and a lower fasting TAG concentration. The combined interventions did not decrease the total or LDL cholesterol concentrations, however by the end of the treatment both groups had increased HDL-cholesterol concentrations compared to baseline and each individual treatment at week four. Most significantly our findings suggest that the combined effect of the chronic exercise and fish oil was sufficient to alter the basal metabolism of chylomicrons in these viscerally obese subjects.
The reduction of fasting TAG that occurred when the interventions were combined corresponds with suggestions in the literature that both exercise and fish oil could individually reduce VLDL production [15, 35], mainly by suppressing hepatic lipogenesis. The combined interventions also lowered the postprandial TAG response. A reduction in fasting VLDL production could have facilitated the lower postprandial TAGIAUC response as a result of less competition with the exogenous TAG for lipid clearance mechanisms. The lipaemic reduction is also likely because of increased lipoprotein lipase activity in adipose tissue following fish oil  or in the leg muscle after exercise . As a result of chronic training adaption, exercise is also suggested to promote lipid clearance by increasing capillary vascularisation [37, 38], as was expected after 12 weeks of regular walking. Since chylomicrons are the preferred substrate for lipoprotein lipase, it is likely that our combined interventions affected chylomicron delipidation in the early postprandial phase and then the VLDL that predominates later in the postprandial excursion . Hydrolysis from both hepatic and intestinal lipoproteins is likely to be a pivotal mechanism in the postprandial TAG reduction.
The effect of fish oil significantly lowered the TAGIAUC response even without exercise. In animals and humans, fish oil accelerates catabolism of VLDL to LDL  through enhancing blood circulation to capillary lipases, lipase binding or expression [39–41]. Such catabolic changes correspond to our results of an increased LDL cholesterol concentration initially after four weeks of fish oil. Others reporting similar findings after four and six weeks of fish oil have proposed that this increase might be in the LDL1 fraction rather the small dense particles [42, 43] which suggests that measuring plasma lipids following fish oil in the longer term (i.e. chronic interventions) may be more physiological useful than shorter studies. Interestingly we also reported increases in glucose concentration and HOMA score with the four weeks of fish oil, findings which are also reported in the literature. Woodman et al.  measured interim blood glucose concentrations at three weeks during their six week n-3 FA trial and discuss a transient adverse trend in glycaemic control, which was corrected by the end of the trial. As did Mori and colleagues , who suggest that the variability in the effect of fish oil on glycaemic control may arise from varying degrees of insulin sensitivity between subjects and the presence of other disorders including hypertension and obesity. By the time our subjects had undergone the additional exercise at week 16, the fish oil-associated HOMA increase was abolished, consistent with earlier findings . However based on the present results, it would be prudent to suggest that insulin resistant patients monitor their glycaemic control when commencing fish oil supplements, and incorporate regular, moderate intensity exercise into their lifestyle.
Our key finding was that fish oil plus chronic exercise did modulate the basal metabolism of apo B48, a finding not reported elsewhere in the literature. This finding is important since chylomicron homeostasis is more difficult to modulate than that of hepatic lipoproteins . The fasting apo B48 concentration represents the difference between the constitutive secretion rate and the clearance rate of the lipid-poor remnants. Suggestions from cell, animal and human studies is that fish oil and exercise could modulate both the clearance of apo B48 remnants [22, 47–52], and also play a role in reducing apo B48 secretion .
Our results have shown that a combined fish oil and exercise intervention may be effective in reducing fasting apo B48 in otherwise free-living, insulin resistant subjects. The interaction between fish oil and exercise may be hinged on the fact that our subjects were insulin resistant throughout the study. Insulin resistance may have contributed to an over-secretion of intestinal apo B  as well as compromised the receptor-mediated uptake of apo B48 in our subjects. Another feature of insulin resistance is the association with inflammatory markers (e.g. C-reactive protein, prostaglandin PGE2, pro-inflammatory cytokines)  and high oxidative stress . Liver cell culture studies suggest that this stress may impact chylomicron remnant uptake . Therefore it is plausible that by improving our subjects' oxidative status through 12 weeks of regular exercise [56, 57], and long-term fish oil [58–61] we may have somewhat corrected the defective uptake of chylomicron remnants by the liver in separate but related mechanisms. A further suggestion from cell culture studies is that when the oxidative status of the liver was improved, the degree of improvement to remnant uptake was even more enhanced when remnants were enriched with n-3 FA . This suggestion might allude to why in our human study the basal apo B48 concentration was only lower when the fish oil and chronic exercise were added together.
We therefore conclude that an effective therapeutic strategy for the chylomicronaemia in subjects with MetS is the combination of chronic, regular exercise and a relatively low dose of fish oil. We also note that these benefits occurred even without insulin resistance being completely normalised. The mechanisms through which these two interventions work are likely to be different, which may be why they were efficacious only when used in combination. While our study was not intended to test the mechanisms, further investigation is warranted to decipher the reasons that chronic exercise and fish oil reduce basal apo B48 concentration in insulin resistant men.