Genetic ablation of miR-33 increases food intake, enhances adipose tissue expansion, and promotes obesity and insulin resistance

While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies, and predisposition of miR-33-/- mice to obesity and metabolic dysfunction, exemplify the possible pitfalls of miRNA based therapies. Our work provides an in-depth characterization of miR-33-/- mice, and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1 mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33-/- mice we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals. Wild-type (WT) and mir-33 knockout (KO) male mice were fed a standard chow diet for 8-10 weeks after which they were either switched to a high fat diet (HF, 60% calories from fat: Research Diets D12492) for 20 weeks or maintained on chow diet (CHOW). For fasting-refeeding experiments, mice were either sacrificed at 8:00am after overnight feeding (FED), after being fasted for 24 h beginning at 8:00am (FAST), or after being fasted for 24 h beginning at 8:00pm followed by 12 h of feeding overnight (FED2X). Each group is represented by four biological replicates.