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High fat diets decrease glucose tolerance and increase insulin resistance at peripheral tissues such as adipose and muscle. Fish oils, containing a high concentration of ω3 fatty acids, have been reported to counter the development of insulin resistance in rats in response to high fat diets. Because fish oils contain a number of long chain fatty acids that may be mediating this response, we investigated the specific effects of docosahexaenoic acid (DHA), which comprises approximately 10% of the fatty acids in fish oils, on the hormonal regulation of glucose uptake in isolated adipocytes. Weanling rats were fed diets containing 12% of calories as corn oil (LF-CO), or 26% of calories as safflower oil (ω6 rich, MF-SO) or DHASCO ™ (44.6% DHA, MF-DHA). Feed consumption and growth did not differ between the dietary treatments. After 8 weeks of feeding, fasting serum glucose levels were higher in both the high fat diet groups compared to LF-CO. Basal uptake of 2.5 mM [ 3 H]-2-deoxyglucose (2DG) was reduced in MF-DHA compared to LF-CO. Insulin stimulated 2-DG uptake in all three diet groups. However, despite this stimulus, uptake was lower in MF-SO rats and further reduced in MF-DHA rats. Decreased insulin-stimulated uptake was associated with a reduction in total quantity of GLUT4 in MF-SO rats, but was independent of any change in GLUT4 in MF-DHA fed rats. The β-adrenergic agonist, isoproterenol, decreased 2DG uptake in insulin-stimulated adipocytes by 51% and 36%, respectively, in the LF-CO and MF-SO groups, but had no effect after MF-DHA feeding. This loss of β-adrenergic responsiveness was associated with a decrease in quantity of immunoreactive Gα s protein. These data indicate that long-term feeding of MF-DHA diets impaired basal glucose disposal and disrupted normal hormonal regulation of glucose uptake by the adipocyte.

We wanted to examine the effects of an oil rich in docosahexaenoic acid (DHA), without eicosapentaenoic acid, on the composition of membrane phospholipid in a variety of tissues. Our in vitro studies had previously shown that DHA could modify glucose and nucleoside transport in cells in culture and also increase selectivity of the nucleoside drug, arabinosylcytosine (araC) toward tumor cells. Here we wanted to examine what effect DHA supplementation would have in the whole animal in terms of the chemosensitivity of normal bone marrow, the dose-limiting tissue during chemotherapy, to araC. The purpose was to determine whether fatty acid supplementation might be useful as an adjuvant to chemotherapy. We fed diets containing 5% (w/w) low fat-corn oil (LF-CO group), 10% moderate fat-safflower oil (MF-SO group), or 10% DHASCOTM (MF-DHA group) to weanling Fischer 344 rats for 8–9 wk. Feed intake and growth were not different between the different diets. Similarly, treatment of animals with the chemotherapeutic drug araC did not differentially affect growth, feed intake, or tissue fatty acid composition for the different diet groups. Fatty acid compositions of bone marrow, liver, red blood cells, plasma phospholipid and triglyceride, as well as skeletal and cardiac muscle, were substantially different between the dietary groups. The DHASCOTM oil contained 46% DHA (22:6n-3) and resulted in profound incorporation of DHA in all tissues examined. The most dramatic response was seen in skeletal muscle of MF-DHA fed animals where DHA represented 46% of membrane phospholipid fatty acids. This is likely to have consequences to muscle function. Although DHASCOTM contains a similar level of saturated fatty acids (42%), few differences in saturates were noted between the various dietary groups for most of the tissues examined. Both LF-CO and MF-SO diets were hypercholesterolemic, and the LF-CO was also hypertriglyceridemic compared to the chow-fed animals. Animals fed the MF-DHA diet had the lowest triglyceride levels of any of the treatment groups and cholesterol levels comparable to chow-fed animals. MF-DHA had substantially higher numbers of colony-forming units-granulocyte macrophage (CFU-GM) as reflected in a twofold higher bone marrow cellularity than either chow or LF-CO animals, suggesting expansion of the bone marrow compartment with DHA feeding. Although higher than LF-SO, the number of CFU-GM in MF-SO animals was not significantly higher than animals fed chow. Bone marrow from LF-CO animals appeared to be more resistant to araC treatment than either MF group. Thus, DHA, fed as DHASCOTM, has advantages over low or moderate n-6 diets and chow as it is has both hypolipidemic- and bone marrow-enhancing properties in weanling Fischer 344 rats. This suggests that DHA supplementation may be useful in adjuvant chemotherapy.

Fischer 344 rats were inoculated with fibrosarcoma tumor cells and fed diets containing 5% or 10% (wt/wt) safflower oil or 10% oil containing docosahexaenoic acid (DHA). Animals were then treated with arabinosylcytosine (araC) or saline for six days. Tumor weights were highest in animals fed 10% safflower oil and treated with saline, intermediate in animals fed oil containing DHA and 5% safflower oil and treated with saline, and lowest in araC-treated animals from all diets. Plasma cholesterol and triglyceride levels correlated highly with final tumor size, regardless of diet or treatment group. Animals fed safflower oil had lower intestinal weights than those fed DHA, which histology demonstrated to be a result of differences in villus height and crypt depth. Substantial loss of bone marrow cells occurred in all dietary groups treated with araC; however, the proportion of granulocyte-macrophage precursors remaining in the DHA animals was higher than in saline-treated animals and twofold higher than in the animals fed 10% safflower oil and treated with araC. These data suggest that, even in the face of rapid tumor growth and chemotherapeutic challenge, consumption of a diet rich in DHA can slow tumor growth, prevent hyperlipidemia, enhance bone marrow cellularity, and promote intestinal growth compared with a moderate-fat n--6-rich diet.