br Other Alterations in Triglyceride Metabolism in DGAT Defi
Other Alterations in Triglyceride Metabolism in DGAT-Deficient Mice Consistent with the enzyme\'s ubiquitous expression pattern, DGAT deficiency also altered triglyceride metabolism in other tissues. For example, postpartum Dgat−/− female mice were unable to nurse their young owing to an absence of milk production, implying that DGAT plays a crucial role in lactation (Smith et al. 2000). Preliminary observations also indicate that DGAT deficiency results in changes in triglyceride metabolism in the skin, liver, and small intestine (S. Smith and R. Farese, Jr., unpublished data). These observations will require further investigation, especially if DGAT inhibition is to be explored as a potential therapy for obesity in humans.
Conclusions The generation of DGAT-deficient mice has provided a better understanding of triglyceride synthesis and its relationship to obesity. Further, the obesity resistance, increased Disuflo Cy5 azide expenditure, and apparently improved glucose metabolism associated with DGAT deficiency suggest that DGAT inhibition may be a worthwhile strategy for treating obesity. As an enzyme, DGAT is an excellent target for a small molecule inhibitor. Indeed, inhibitors of the ACAT members of systematics gene family already exist (Krause and Bocan 1995). Although there are currently no known synthetic inhibitors of DGAT, several naturally occurring compounds have been reported to inhibit DGAT activity Rustan et al. 1988, Tabata et al. 1997, Tomoda et al. 1999. Thus, one option for obesity treatment in the future may be similar to the current treatment strategy for hypercholesterolemia with HMG-CoA reductase inhibitors (i.e., inhibition of a key enzyme in a lipid biosynthetic pathway). Nonetheless, enthusiasm for the potential benefits of DGAT inhibition must be tempered by the reality that few newly identified therapeutic targets develop to the stage of clinical trials. Additionally, the degree to which DGAT would have to be inhibited and whether this inhibition would cause side effects are unclear.