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Biochemical and Molecular Actions of Nutrients

A Fish Oil Diet Does Not Reverse Insulin Resistance despite Decreased Adipose Tissue TNF- Protein Concentration in ApoE-3*Leiden Mice¹

Martin Muurling^*,, Ronald P. Mensink, Hanno Pijl^**, Johannes A. Romijn, Louis M. Havekes^*,** and Peter J. Voshol^*,,2

^* TNO-Prevention and Health, Gaubius Laboratory Leiden, 2301 CE Leiden, The Netherlands; Department of Human Biology/NUTRIM, Maastricht University, 6200 MD Maastricht, The Netherlands; ^** Departments of Cardiology and Internal Medicine and Department of Endocrinology and Diabetes, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

²To whom correspondence and reprint requests should be addressed. E-mail: pj.voshol{at}pg.tno.nl.

Dietary interventions with fish oil have been found to protect against the development of high-fat diet-induced insulin resistance and to decrease the expression of tumor necrosis factor (TNF)-. However, the effect of fish oil administration on preexisting insulin resistance is subject to debate. In the present study, we examined the mechanism by which fish oil affects preexisting insulin resistance. High fat diet–induced insulin-resistant ApoE*3-Leiden transgenic mice were treated for 10 wk as follows: 1) high fat diet (control group), 2) high fat diet with 3 g/100 g fish oil and 3) high fat diet but food intake restricted to 75% of the ad libitum food intake. We measured plasma glucose, insulin, free fatty acids (FFA) and triglyceride (TG) levels throughout the study. After the 10-wk dietary intervention period we performed hyperinsulinemic euglycemic analyses and measured insulin sensitivity and FFA turnover. Furthermore, we then determined the VLDL-TG production rate and TNF- protein expression in white adipose tissue (WAT). Compared with control mice, the insulin sensitivity of mice treated with fish oil was not affected, whereas it was improved (P < 0.05) for energy-restricted mice. FFA turnover was unaffected in both fish oil–treated and energy-restricted mice. Compared with controls, hepatic VLDL-TG production was lower (P < 0.05) with fish oil feeding but greater with energy restriction (P < 0.05). Interestingly, the level of TNF- protein in WAT was lower (P < 0.05) in both groups. We conclude that partial replacement of saturated fat by fish oil does not improve preexisting high fat diet-induced insulin resistance, although it lowers TNF- protein levels in WAT.

KEY WORDS: • fish oil • insulin resistance • insulin sensitivity • free fatty acid metabolism • tumor necrosis factor-

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