MicroRNA-155 Deficiency Leads to Decreased Atherosclerosis, Increased White Adipose Tissue Obesity, and Non-alcoholic Fatty Liver Disease

Abstract

Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE mice, and miR-155 deficiency in apoE mice inhibits atherosclerosis; 2) apoE/miR-155 (double knock-out (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP 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 OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.

miR155 deficiency aggravates high-fat diet-induced adipose tissue fibrosis in male mice

“…This is further supported by the differences in fat mass between the miR155 −/− and WT LFD mice; miR155 −/− LFD mice had more body fat compared to the WT LFD mice, yet no differences in visceral fat were evident (similar to the finding of Virtue et al. ()). miR155 also has been shown to be a negative regulator of brown adipose tissue function and white adipose tissue “browning”(Chen et al.…”

“…Virtue et al. (), however, found no such effect as both miR155 −/− and WT HFD‐fed mice displayed a similar amount of gonadal fat accretion. Furthermore, our results, as well as those of Gaudet et al.…”

“…Virtue et al. (), on the other hand, found that miR155 deficiency in female mice led to a similar body weight gain and body fat accumulation as WT‐HFD‐fed mice and Lin et al. () discovered that miR155 −/− female mice exposed to an HFD actually displayed impaired glucose metabolism and insulin signaling compared to WT HFD‐fed controls.…”

“…), while a recently published study found no such effect (Virtue et al. ). Additionally, a study by Csaket al.…”

“…However, the influence that miR155 has on obesity development, including in vivo macrophage behavior, adipose tissue physiology, and glucose metabolism remains poorly understood and published findings are equivocal. For example, miR155 deletion has been shown to prevent diet-induced obesity in a sex-dependent manner , while a recently published study found no such effect (Virtue et al 2016). Additionally, a study by Csaket al (2015) indicated that miR155 deficiency attenuated nonalcoholic fatty-liver disease (NAFLD), a condition typically associated with obesity, yet in another model of NAFLD, deletion of miR155 augmented NAFLD development (Miller et al 2013).…”