Over-expression of monoacylglycerol lipase (MGL) in small intestine alters endocannabinoid levels and whole body energy balance, resulting in obesity.

The function of small intestinal monoacylglycerol lipase (MGL) is unknown. Its expression in this tissue is surprising because one of the primary functions of the small intestine is to convert diet-derived MGs to triacylglycerol (TG), and not to degrade them. To elucidate the function of intestinal MGL, we generated transgenic mice that over-express MGL specifically in small intestine (iMGL mice). After only 3 weeks of high fat feeding, iMGL mice showed an obese phenotype; body weight gain and body fat mass were markedly higher in iMGL mice, along with increased hepatic and plasma TG levels compared to wild type littermates. The iMGL mice were hyperphagic and displayed reduced energy expenditure despite unchanged lean body mass, suggesting that the increased adiposity was due to both increased caloric intake and systemic effects resulting in a hypometabolic rate. The presence of the transgene resulted in lower levels of most MG species in intestinal mucosa, including the endocannabinoid 2-arachidonoyl glycerol (2-AG). The results therefore suggest a role for intestinal MGL, and intestinal 2-AG and perhaps other MG species, in whole body energy balance via regulation of food intake as well as metabolic rate.

Intestinal mucosal triacylglycerol accumulation secondary to decreased lipid secretion in obese and high fat fed mice.

The ectopic deposition of fat in liver and muscle during obesity is well established, however surprisingly little is known about the intestine. We used the ob/ob mouse and C57BL6/J mice fed a high fat (HF) diet to examine the effects of obesity and the effects of HF feeding, respectively, on intestinal mucosal triacylglycerol (TG) accumulation. Male C57BL6/J (wild-type, WT) mice were fed low fat (LF; 10% kcal as fat) or HF (45%) diets, and ob/ob mice were fed the LF diet, for 3 weeks. In this time frame, the WT-HF mice did not become obese, enabling independent examination of effects of the HF diet and effects of obesity. Analysis of intestinal lipid extracts from fed and fasted animals demonstrated that the mucosa, like other tissues, accumulates excess lipid. In the fed state, mucosal triacylglycerol (TG) levels were threefold and fivefold higher in the WT-HF and ob/ob mice, respectively, relative to the WT-LF mice. In the fasted state, mucosa from ob/ob mice had threefold higher TG levels relative to WT-LF mucosa. q-PCR analysis of mucosal mRNA from fed state mice showed alterations in the expression of several genes related to both anabolic and catabolic lipid metabolism pathways in WT-HF and ob/ob mice relative to WT-LF controls. Fewer changes were found in mucosal samples from the fasted state animals. Remarkably, oral fat tolerance tests showed a striking reduction in the plasma appearance of an oral fat load in the ob/ob and WT-HF mice compared to WT-LF. Overall, the results demonstrate that the intestinal mucosa accumulates excess TG during obesity. Changes in the expression of lipid metabolic and transport genes, as well as reduced secretion of dietary lipid from the mucosal cells into the circulation, may contribute to the TG accumulation in intestinal mucosa during obesity. Moreover, even in the absence of frank obesity, HF feeding leads to a large decrease in the rate of intestinal lipid secretion.