Mice subjected to aP2-Cre mediated ablation of microsomal triglyceride transfer protein are resistant to high fat diet induced obesity.

Background: Microsomal triglyceride transfer protein (MTP) is essential for the assembly of lipoproteins. MTP has been shown on the surface of lipid droplets of adipocytes; however its function in adipose tissue is not well defined. We hypothesized that MTP may play critical role in adipose lipid droplet formation and expansion.

Methods: Plasmids mediated overexpression and siRNA mediated knockdown of Mttp gene were performed in 3T3-L1 pre-adipocytes to evaluate the effects of MTP on cell differentiation and triglyceride accumulation. Adipose-specific knockdown of MTP was achieved in mice bybreeding MTP floxed (Mttp (fl/fl) ) mice with aP2-Cre recombinase transgenic mice. Adipose-specific MTP deficient (A-Mttp (-/-) ) mice were fed 60 % high-fat diet (HFD), and the effects of MTP knockdown on body weight, body fat composition, plasma and tissues lipid composition, glucose metabolism, lipogenesis and intestinal absorption was studied. Lipids were measured in total fasting plasma and size fractionated plasma using colorimetric assays. Gene expression was investigated by Real-Time quantitative PCR. All data was assessed using t-test, ANOVA.

Results: MTP expression increased during early differentiation in 3T3-L1 cells, and declined later. The increases in MTP expression preceded PPARγ expression. MTP overexpression enhanced lipid droplets formation, and knockdown attenuated cellular lipid accumulation. These studies indicated that MTP positively affects adipogenesis. The ablation of the Mttp gene using aP2-Cre (A-Mttp (-/-) ) in mice resulted in a lean phenotype when fed a HFD. These mice had reduced white adipose tissue compared with wild-type Mttp (fl/fl) mice. The adipose tissue of A-Mttp (-/-) mice had increased number of smaller size adipocytes and less macrophage infiltration. Further, these mice were protected from HFD-induced fatty liver. The A-Mttp (-/-) mice had moderate increase in plasma triglyceride, but normal cholesterol, glucose and insulin levels. Gene expression analysis showed that the adipose tissue of the A-Mttp (-/-) mice had significantly lower mRNA levels of PPARγ and its downstream targets.

Conclusion: These data suggest that MTP might modulate adipogenesis by influencing PPARγ expression, and play a role in the accretion of lipids to form larger lipid droplets. Thus, agents that inactivate adipose MTP may be useful anti-obesity drugs.