Synthesis of fat in response to alterations in diet: insights from new stable isotope methodologies

Synthesis of fatty acids, or de novo lipogenesis (DNL), is an intensively researched metabolic pathway whose functional significance and metabolic role have nevertheless remained uncertain. Methodologic problems that limited previous investigations of DNL in vivo and recent methodologic advances that address these problems are discussed here. In particular, deuterated water incorporation and mass isotopomer distribution analysis techniques are described. Recent experimental results in humans based on these techniques are reviewed, emphasizing dietary and hormonal factors that modulate DNL and quantitative significance of DNL under various conditions, including carbohydrate overfeeding. The somewhat surprising finding that DNL appears not to be a quantitatively major pathway even under conditions of surplus carbohydrate energy intake, at least in normal adults on typical Western diets, is discussed in depth. Nutritional and metabolic implications of these results are also noted, and some speculations on possible functional roles of DNL in normal physiology and disease states are presented in this context. In summary, methodologic advances have added to our understanding of DNL and its regulation, but many questions concerning quantitation and function remain unanswered.