Date of Award
Open Access Dissertation
Obesity is an inflammatory disease involving accumulation of adipose tissue, gut microbiota dysbiosis, and over-activation of the endocannabinoid system (ECS). Mechanisms involved in ECS regulation of obesity-induced inflammation are not well understood. Presented here are three chapters involving microRNA (miR) regulation of inflammatory adipose tissue macrophages (ATM) during high-fat diet (HFD)-induced obesity and cannabinoid receptor-mediated regulation of gut microbiota dysbiosis.
ATMs are innate immune cells that drive chronic low-grade inflammation during obesity. Polarization between pro-(M1) and anti-(M2-like) inflammatory phenotypes influence insulin sensitivity and energy expenditure; however, the mechanisms involved are unclear. In study one, we characterized miRs involved in ATM polarization during diet-induced obesity (DIO). In study two, DIO mice were treated with the cannabinoid receptor 1 (CB1) antagonist AM251 because CB1 antagonists ameliorate DIO and associated inflammation. In both studies, it was found that the miR-30 family regulates ATM Delta-like-4 (DLL4)-Notch signaling, and consequently ATM polarization. Downregulation of miRs 30a-5p, 30c-5p, and 30e-5p in ATMs from DIO mice versus lean mice resulted in Notchsignaling induced M1 polarization. Interestingly, miR-30e-5p was upregulated in ATMs from DIO mice treated with AM251, while DLL4 was downregulated. Subsequently, fat storage and M1 ATM polarization was reduced. Furthermore, AM251-treated macrophages suppressed DLL4-mediated Th1 polarization in CD4+ T cells. The combined effect of miR-30 in ATMs and consequently T cells led to an anti-inflammatory state and attenuation of diet-induced obesity regulated by CB1 blockade.
In the third study, CB1-/- and CB2-/- mice as well as AM251 DIO intervention were used to investigate ECS regulation of DIO-associated gut dysbiosis. CB1-/- mice displayed resistance, whereas, CB2-/- mice displayed accelerated DIO development versus wild-type (WT) mice. Interestingly, CB1 and CB2 reciprocally regulated HFD-induced leukocyte infiltration in the cecal-colonic lamina propria. Microbiota profiling showed that CB1-/-, but not WT or CB2-/- mice were resistant to development of HFD-induced gut dysbiosis. Moreover, AM251 intervention in obese mice shifted their microbiota towards a lean profile. Investigation of host: microbiota interactions revealed ECS-mediated regulation of intestinal barrier defense and gut microbiota-mediated sugar metabolism were involved in the pathogenesis of obesity.
Miranda, K.(2019). Role of Epigenome and Microbiome in Endocannabinoid-Mediated Regulation of Inflammation During Diet-Induced Obesity. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5391