Mice Lacking Both Cannabinoid-1 and Cannabinoid-2 Receptors Are Resistant to Diet-Induced Obesity

Abstract

Exogenous cannabinoids are a group of related compounds derived from the Cannabis plant, commonly known as marijuana. The discovery of cannabinoid receptors (CB1R and CB2R) has provided a platform for investigating the health effects of cannabinoids. The CB1R is predominantly expressed in the central nervous system, whereas CB2R is primarily expressed in the immune system. Mounting evidence has shown that activation of CB1 is associated with increased food intake and obesity, whereas activation of CB2 is associated with decreased levels of cytokines associated with insulin resistance and type 2 diabetes (T2D). Epidemiological studies, however, have shown a decreased prevalence of obesity and T2D among cannabis users. Here we use high-fat diet (HFD, 45% of calories from fat vs. control LFD with 10% of calories from fat) to study the metabolic changes in male mice lacking receptors of the cannabinoid system (CB-DKO) when compared to wild type (WT) C57BL/6 mice. Eight-weeks old CB-DKO mice displayed lower body fat percent and higher percent of lean mass tissue when compared to WT mice. After 12 weeks, WT mice gained an average of 22 grams on HFD compared to 9 grams on LFD. CB-DKO mice did not respond to HFD, gaining an average of 5 grams on both HFD and LFD. This corresponded to a 5% increase in body fat in CB-DKO mice compared to 18% increase in WT mice. Glucose tolerance test indicated increased insulin sensitivity in CB-DKO mice. Automated measurements revealed no significant differences in food intake or locomotion between CB-DKO and WT mice, whereas CB-DKO mice displayed higher indirect calorimetry parameters including VO2, respiratory exchange ratio, and energy expenditure. Gene expression analysis confirmed an upregulation of thermogenic genes (UCP1, CIDEA, and COX8B) suggesting browning of white adipose tissue in CB-DKO mice. These findings highlight the role of the cannabinoid system in metabolic control of adipose tissues and their potential role for insulin resistance and T2D risk. Disclosure O. Alshaarawy: None. E. Kurjan: None. N. Truong: None. L.K. Olson: None.