Loss of regulation of lipogenesis in the Zucker diabetic (ZDF) rat

We present here a study on the role of leptin in the regulation of lipogene sis by examining the effect of dietary macronutrient composition on lipogen esis in the leptin receptor-defective Zucker diabetic fatty rat (ZDF) and i ts lean litter mate (ZL). Animals were pair fed two isocaloric diets differ ing 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 mac ronutrient 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 w as normally suppressed in response to the high-fat diet in the ZL rat to ma intain 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.