Abstract
ObjectiveMicroRNA (miR)−34a 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.MethodsWild‐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.ResultsHFD‐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, Lxrα, Pgc1α, and Fasn. miR‐34a−/− intrascapular brown adipose tissue had basal reductions in c/ebpα and c/ebpβ, with in vitro miR‐34a−/− white adipocytes showing increased lipid content. An F4/80high 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‐α.ConclusionsThese findings suggest a multifactorial role of miR‐34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways.
Highlights
The growing incidence of obesity worldwide has presented new therapeutic challenges, making it critical to understand the underlying mechanisms of obesity-associated pathology
In situ hybridization showed miR-34a distribution within visceral white adipose tissue (WAT) was ubiquitous throughout the epididymal (e)WAT of WT mice on chow and high-fat diet (HFD) and omental adipose from bariatric surgery patients with obesity (Figure 1A)
We observed an increase in miR-34a (P 5 0.0086) and miR-34a* (P 5 0.0461) transcripts in WT bone marrowderived macrophages (BMDMs) when stimulated with tumor necrosis factor (TNF)-a (Figure 1D)
Summary
The growing incidence of obesity worldwide has presented new therapeutic challenges, making it critical to understand the underlying mechanisms of obesity-associated pathology. Obesity is associated with increased low-grade, chronic inflammation that predisposes individuals to a number of comorbidities, e.g., type 2 diabetes (T2D), dyslipidemia, cardiovascular diseases (CVDs), and cancers [1,2]. The main proponent of weight gain during obesity is white adipose tissue (WAT). Brown adipose tissue (BAT) expends fatty acids (FA) to produce heat through mitochondrial action and uncoupled protein 1 (UCP1), maintaining body temperature. Peroxisome proliferator-activated receptor (PPAR)-c coactivator (PGC)21a is important for BAT adaptive thermogenesis, increasing mitochondrial biogenesis and UCP1 expression and promoting brown adipocyte differentiation [4]
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