The role of monoglyceride lipase in the intestine

The current epidemic of obesity and its comorbidities, as consequence of increased consumption of fat and energy-rich food, has led to renewed interest in the role of the intestine in the regulation of lipid homeostasis. Lipases are essential in the uptake of dietary lipids, their distribution within the body, their mobilization, and remodeling for further metabolization. Monoglyceride lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoglycerides (MGs) derived from different intra- and extracellular sources. These MGs are not only intermediate products of lipid degradation but are also signaling molecules or serve as precursors for the synthesis thereof. We and others showed previously that MGL-deficiency protects from high-fat diet (HFD) induced obesity insulin resistance. However, the exact mechanisms by which MGL affects whole body lipid and glucose homeostasis remain elusive. Our preliminary data suggest that MGL plays a role in intestinal MG metabolism since MGL-deficient mice are more sensitive to lipid-induced constipation, and exhibit prolonged whole gut transit when fed a HFD. We assume that MGL-deficiency affects lipid absorption and intestinal hormone signaling and consequently improves whole body energy and lipid balance. Therefore, the overall aim of this proposal is to characterize the role of MGL in intestinal MG catabolism. For that purpose, we will characterize mice lacking MGL specifically in the intestine. We will study the role of intestinal MGL upon chow and HFD feeding. Moreover, we will investigate gut motility, gut function, and lipid absorption in vivo and in vitro, and we will investigate MG mediated hormone signaling. Together, these studies will define whether pharmacological inhibition of intestinal MGL qualifies as a novel therapeutic target for the treatment of obesity and insulin resistance by regulating intestinal lipid metabolism and hormone signaling.