Characterization of mice with tissue-specific deletion of monoglyceride lipase

The proposed investigations are primarily focused on the role of monoglyceride lipase (MGL) in energy metabolism. MGL is considered as rate-limiting enzyme in the hydrolysis of monoacylglycerol (MG) deriving from the degradation of triglycerides or glycerophospholipids. Current evidence suggests that MGL influences metabolism by at least two different mechanisms: First, MGL catalyzes the final step in lipolysis in adipose tissue as well as in other tissues and thereby affects the concentration of circulating lipids and glycerol levels which can affect energy homeostasis and insulin signaling. Second, MGL is involved in the degradation of 2- arachidonoylglycerol (2-AG), the most abundant endocannabinoid (EC) in the body. 2-AG activates cannabinoid receptors (CBR) and can influence energy metabolism by modulating behavioral and metabolic processes. Moreover, it has been postulated that aberrant EC signaling contributes to the development of metabolic diseases. Based on this dual function of MGL, we hypothesize that the systemic lack of MGL affects energy homeostasis in a very complex way. The objective of this proposal is to generate and to characterize mice lacking MGL specifically in adipocytes, neurons, or glial cells. Using these mouse models, we should able to investigate the tissue-specific role of MGL in endocannabinoid metabolism and lipolysis.

Cannabis sativa has been used as an agent for achieving euphoria and for medical purposes since ancient times and is still used in modern medicine. Important medical applications are based on the antiemetic, appetite-stimulating, and anti-nociceptive effects of cannabinoids. Furthermore, cannabinoids have neuroprotective potential in the case of traumatic brain injury or neurodegenerative diseases. In addition to the use of cannabis-based drugs, the possibility exists to activate the endogenous cannabinoid system of the body, which is designated as endocannabinoid system. This system comprises endogenous mediators, known as endocannabinoids, and cannabinoid receptors that can be activated by endo- as well as plant cannabinoids. By manipulating the endocannabinoid system it is possible to mimic the effects of cannabinoids without treating the organism with cannabis-based drugs. This strategy is highly interesting for medical purposes, because it may prevent side effects of cannabis-based drugs. In this project, we investigated the effects of an endocannabinoid in mouse models. For this purpose, we deleted the enzyme monoglyceride lipase (MGL) by genetic manipulation. MGL is responsible for the degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) and its inactivation leads to strongly elevated 2-AG concentrations. Our observations demonstrate that increased 2-AG levels cause similar effects as observed in response to chronic cannabinoid treatment. They activate the endocannabinoid system finally leading to desensitization of cannabinoid receptors in brain and intestine. Furthermore, we observed that inactivation of MGL causes has anti-inflammatory effects by reducing the synthesis of pro-inflammatory prostaglandins. The findings of our study provide important insights about the pharmacological effects of drugs affecting endocannabinoid metabolism.