miR-34a-/- Mice are Susceptible to Diet-Induced Obesity

Objective: MicroRNA (miR) 234a regulates inflammatory pathways, and increased transcripts have been observed in serum and subcutaneous adipose of subjects who have obesity and type 2 diabetes. Therefore, the role of miR-34a in adipose tissue inflammation and lipid metabolism in murine diet-induced obesity was investigated. Methods: Wild-type (WT) and miR-34a(-/-) mice were fed chow or high-fat diet (HFD) for 24 weeks. WT and miR-34a(-/-) bone marrow-derived macrophages were cultured in vitro with macrophage colony-stimulating factor (M-CSF). Brown and white preadipocytes were cultured from the stromal vascular fraction (SVF) of intrascapular brown and epididymal white adipose tissue (eWAT), with rosiglitazone. Results: HFD-fed miR-34a(-/-) mice were significantly heavier with a greater increase in eWAT weight than WT. miR-34a(-/-) eWAT had a smaller adipocyte area, which significantly increased with HFD. miR-34a(-/-) eWAT showed basal increases in Cd36, Hmgcr, Lxr alpha, Pgc1 alpha, and Fasn. miR-34a(-/-) intrascapular brown adipose tissue had basal reductions in c/ebp alpha and c/ebp beta, with in vitro miR-34a(-/-) white adipocytes showing increased lipid content. An F4/80(high) macrophage population was present in HFD miR-34a(-/-) eWAT, with increased IL-10 transcripts and serum IL-5 protein. Finally, miR-34a(-/-) bone marrow-derived macrophages showed an ablated CXCL1 response to tumor necrosis factor-alpha. Conclusions: These findings suggest a multifactorial role of miR-34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways.