Loss of regulation of lipogenesis in the Zucker diabetic rat. II. Changes in stearate and oleate synthesis.

De novo lipogenesis and dietary fat uptake are two major sources of fatty acid deposits in fat of obese animals. To determine the relative contribution of fatty acids from these two sources in obesity, we have determined the distribution of c16 and c18 fatty acids of triglycerides in plasma, liver, and epididymal fat pad of Zucker diabetic fatty (ZDF) rats and their lean littermates (ZL) under two isocaloric dietary fat conditions. Lipogenesis was also determined using the deuterated water method. Conversion of palmitate to stearate and stearate to oleate was calculated from the deuterium incorporation by use of the tracer dilution principle. In the ZL rat, lipogenesis was suppressed from 70 to 24%, conversion of palmitate to stearate from 86 to 78%, and conversion of stearate to oleate from 56 to 7% in response to an increase in the dietary fat-to-carbohydrate ratio. The results suggest that suppression of fatty acid synthase and stearoyl-CoA desaturase activities is a normal adaptive mechanism to a high-fat diet. In contrast, de novo lipogenesis, chain elongation, and desaturation were not suppressed by dietary fat in the ZDF rat. The lack of ability to adapt to a high-fat diet resulted in a higher plasma triglyceride concentration and excessive fat accumulation from both diet and de novo synthesis in the ZDF rat.

Underestimation of gluconeogenesis by the [U-(13)C(6)]glucose method: effect of lack of isotope equilibrium.

Among the many tracer methods to indirectly estimate gluconeogenesis in humans, the [U-(13)C(6)]glucose method as proposed by Tayek and Katz (Am J Physiol Endocrinol Metab 270: E709-E717, 1996; Am J Physiol Endocrinol Metab 272: E476-E484, 1997) has the advantage of being able to simultaneously estimate hepatic glucose output and fractional gluconeogenesis. However, Landau et al. (Landau BR, J Wahren, K Ekberg, SF Previs, D Yang, and H Brunengraber. Am J Physiol Endocrinol Metab 274: E954-E961, 1998) have shown that this method underestimates the rate of gluconeogenesis. The underestimation has been attributed to tracer dilution by other three-carbon substrates and the lack of isotopic steady state. Using a computer simulation of [U-(13)C(6)]glucose infusion, we demonstrate that the lack of isotope equilibrium in both the lactate and glucose compartments contributes substantially to the underestimation of gluconeogenesis. [U-(13)C(6)]glucose experiments were performed with the addition of a primed constant infusion of [U-(13)C(3)]lactate and the delay in M3 glucose equilibrium estimated from the isotopic steady-state value determined by modeling M3 glucose to a single-exponential fit. We found that, even with the addition of [U-(13)C(3)]lactate infusion, the M3 glucose enrichment of the last timed sample was approximately 20% less than the isotopic steady-state value. Thus the lack of isotopic equilibrium of the glucose compartment potentially accounts for 20% of the underestimation of gluconeogenesis. The underestimation of gluconeogenesis using [U-(13)C(6)]glucose without the additional infusion of [U-(13)C(3)]lactate in previous publications is expected to be even greater because of the lack of isotope equilibrium in both the lactate and glucose compartments. These findings are consistent with the results from our computer simulation.