The treatment induced reduction in flux of FFA into hepatic lipid stores at high physiological insulin levels (Table 6) in these habitually hyperphagic/hyperinsulinemic animals would tend to lower local TG synthesis and hepatic TG secretion. Indeed we have previously reported that tesaglitazar (same dose and treatment period as the current study) potently lowers hepatic TG content and hepatic TG secretion in obese Zucker rats [17]. In man a reduction in VLDL TG production is expected to have important antidyslipidemic effects [37]. Reduced hepatic FFA availability might also be a mechanism for the improvement in insulin suppression of HGO [38]. The consequences of lowering fatty acid supply is however unlikely to be limited to the liver. Thus, the marked tesaglitazar induced reduction in FFA flux into skeletal muscles (at hyperinsulinemia) may explain the apparent enhancement in insulin stimulated oxidative glucose disposal in this tissue via the glucose-fatty acid cycle [12]. Furthermore, the reduced muscle FFA flux might also lower accumulation of lipid intermediates potentially reducing interference with insulin signaling [39] which may be the basis for the enhanced insulin stimulated glucose uptake and glycogen synthesis rates.
