Monoacylglycerol lipase deficiency affects diet-induced obesity, fat absorption, and feeding behavior in CB1 cannabinoid receptor-deficient mice.

Abstract

Excess energy intake causes obesity, which leads to insulin resistance and various other complications of metabolic syndrome, including diabetes, atherosclerosis, dyslipidemia, and nonalcoholic fatty liver disease. Although recent studies have depicted altered lipid metabolism as an underlying feature, the detailed mechanisms are still unclear. Here we describe a possible role in high-fat diet (HFD)-induced obesity for monoacylglycerol lipase (MGL), an enzyme that is also known to hydrolyze the endocannabinoid 2-arachidonoylglycerol in brain. MGL-deficient [MGL-knockout (KO)] mice fed a HFD gained less body weight than wild-type mice and were protected from insulin resistance and hepatic steatosis. Food intake and energy expenditure were not altered in MGL-KO mice, but blood triglyceride levels after oral olive oil gavage were suppressed, indicating a role for MGL in intestinal fat absorption. Experiments with cannabinoid receptor type 1 (CB1)/MGL double-KO mice revealed that these phenotypes may include mechanisms that are independent of CB1-receptor-mediated endocannabinoid functions. We also noted that MGL-KO mice had less preference for HFD over normal chow diet. Oral but not intraperitoneal lipid administration strongly suppressed the appetites of MGL-KO and CB1/MGL double-KO mice, but not of wild-type and CB1-KO mice. Appetite suppression was reversed by vagotomy, suggesting involvement of MGL in the gut-brain axis regulation of appetite. Our results provide mechanistic insights of MGL's role in diet-induced obesity, lipid metabolic disorder, and regulation of appetite.-Yoshida, K., Kita, Y., Tokuoka, S. M., Hamano, F., Yamazaki, M., Sakimura, K., Kano, M., Shimizu, T. Monoacylglycerol lipase deficiency affects diet-induced obesity, fat absorption, and feeding behavior in CB1 cannabinoid receptor-deficient mice.

• Authors: Kenji Yoshida, Yoshihiro Kita, Suzumi M Tokuoka, Fumie Hamano, Maya Yamazaki, Kenji Sakimura, Masanobu Kano, Takao Shimizu
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 2 Pg. 2484-2497 (02 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 30265576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Asialoglycoproteins
• Clec10a protein, mouse
• Lectins, C-Type
• Membrane Proteins
• Receptor, Cannabinoid, CB1

Topics

• Animals
• Asialoglycoproteins (deficiency)
• Body Weight
• Diet, High-Fat (adverse effects)
• Eating
• Energy Metabolism
• Fatty Liver (etiology, metabolism, pathology)
• Feeding Behavior
• Insulin Resistance
• Intestinal Absorption
• Lectins, C-Type (deficiency)
• Male
• Membrane Proteins (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (etiology, metabolism, pathology)
• Receptor, Cannabinoid, CB1 (physiology)