Deficiency in Microrna-155 Leads to Reduced Atherosclerosis, Increased Obesity and Nonalcoholic Fatty Liver Disease-A Novel Mouse Model of Metabolically Healthy Obesity

Metabolically healthy obesity (MHO) describes the phenomenon of overweight and obese patients paradoxically retaining a healthy metabolic profile. The molecular mechanisms underlying MHO remain enigmatic partly due to a dearth of animal models mirroring MHO in patients. Using apolipoprotein E knockout (ApoE -/- ) mice on high-fat (HF) diet as an atherosclerotic obesity model, we demonstrated: 1) microRNA-155 (miRNA-155, miR-155) is significantly upregulated in aortas of ApoE -/- mice; and miR-155 deficiency in ApoE -/- mice inhibits atherosclerosis; 2) ApoE -/- /miR-155 -/- (DKO) mice show HF diet-induced obesity, adipocyte hypertrophy and present with nonalcoholic fatty liver disease (NAFLD); 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin, increased expression of adipogenic transcription factors, but lack glucose intolerance and insulin resistance. Our results are the first to present a metabolically healthy obesity (MHO) model using DKO mice with features of decreased atherosclerosis, increased obesity and NAFLD. Our findings suggest the mechanistic role of reduced miR-155 expression in MHO and present a new MHO working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying MHO and provide a new biomarker and novel therapeutic target for MHO-related metabolic diseases.