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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. chain elongation; stearoyl-coenzyme A desaturase; tissue fatty acid composition

Underestimation of gluconeogenesis by the [[U-.sup.13][C.sub.6]]glucose method: effect of lack of isotope equilibrium. Am J Physiol Endocrinol Metab 282: E376-E385, 2002. First published October 16, 2001; 10.1152/ajpendo.00210.2001.--Among the many tracer methods to indirectly estimate gluconeogenesis in humans, the [[U-.sup.13][C.sub.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-.sup.13][C.sub.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-sup.13][C.sub.6]]glucose experiments were performed with the addition of a primed constant infusion of [[U-.sup.13][C.sub.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-.sup.13][C.sub.3]]lactate infusion, the M3 glucose enrichment of the last timed sample was ~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-.sup.13][C.sub.6]] glucose without the additional infusion of [[U-.sup.13][C.sub.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. mathematical modeling; mass isotopomer distribution analysis, stable isotopes

Two techniques of measuring rates of gluconeogenesis based on label redistribution after the introduction of (U-13C)glucose into the whole body were investigated. These techniques were contrasted with methods previously derived for carbon-14 tracers. Results showed that the three approaches (stoichiometric, dilution and combinatorial) are equivalent, provided the same set of assumptions are employed.

Lee, W.-N. Paul, Sara Bassilian, Shu Lim, and Laszlo G. Boros. Loss of regulation of lipogenesis in the Zucker diabetic (ZDF) rat. Am J Physiol Endocrinol Metab 279: E425-E432, 2000.--We present here a study on the role of leptin in the regulation of lipogenesis by examining the effect of dietary macronutrient composition on lipogenesis in the leptin receptor-defective Zucker diabetic fatty rat (ZDF) and its lean litter mate (ZL). Animals were pair fed two isocaloric diets differing in their fat-to-carbohydrate ratio providing 10 and 30% energy as fat. Lipogenesis was measured in the rats using deuterated water and isotopomer analysis. From the deuterium incorporation into plasma palmitate, stearate, and oleate, we determined de novo synthesis of palmitate and synthesis of stearate by chain elongation and of oleate by desaturation. Because the macronutrient composition and the caloric density were controlled, changes in de novo lipogenesis under these dietary conditions represent adaptation to changes in the fat-to-carbohydrate ratio of the diet. De novo lipogenesis was normally suppressed in response to the high-fat diet in the ZL rat to maintain a relatively constant amount of lipids transported. The ZDF rat had a higher rate of lipogenesis, which was not suppressed by the high-fat diet. The results suggest an important hormonal role of leptin in the feedback regulation of lipogenesis. leptin receptor; animal model of diabetes; deuterated water; dietary fat