S. Tay2, J. Guo1, B. W. Warner1 1Washington University,Pediatric Surgery,St. Louis, MO, USA 2Washington University,School Of Medicine,St. Louis, MO, USA
Introduction:
Intestinal epithelial cell (IEC)-specific mammalian target of rapamycin complex 1 (i-mTORC1) regulates IEC cell growth and proliferation. Recently, we found that intestine-specific blockade of i-mTORC1 activity by disrupting Raptor gene expression after small bowel resection in mice led to significant loss of body weight. The purpose of this study was to determine a mechanism for this weight loss.
Methods:
Raptor knockout mice (Villin-CreER(+); Raptor(flox/flox) ) and wild-type littermate mice underwent intraperitoneal injection of tamoxifen to inducibly delete Raptor protein expression selectively in the intestinal epithelium of adult mice. We then placed 8 Raptor knockout and 8 control mice on high fat diet for 5 weeks and measured body composition, food intake, fasting blood glucose, lipid metabolism, and white and brown adipose tissue stores.
Results:
Compared to control mice, Raptor-deficient mice had 46% less white adipose tissue, 30% lower total cholesterol, and 34% lower direct HDL (T test, P < 0.05). Further, the Raptor-deficient mice had 40% less food intake and gained only 14% of baseline weight over 5 weeks, compared to 40% weight gain in control mice. Interestingly, fecal fat content, fasting blood glucose, and brown adipose tissue were not affected. Our results suggest that the decreased body weight gain following i-mTORC1 inactivation is not due to glucose response or lipid absorption or excretion, instead it is strongly associated with reduced food intake.
Conclusion:
The finding of reduced food intake due to an intestinal epithelial cell-specific gene disruption is novel. Prior studies have looked at satiety and adiposity signals such as cholecystokinin, insulin, and leptin, but the drastic decrease in food intake coupled with normal glucose response and lipid absorption observed in Raptor knockout mice could not be explained by either of these signals. While gut microbiota has been found to modulate gut-brain interaction and food intake, and we cannot rule out the effects of commensal bacteria, the remarkable suppression of food intake seen in Raptor knockout mice suggests that an internal pathway may underlie such phenomenon. Future studies are planned to investigate this pathway.