Vascular endothelial growth factor A (VEGF) is highly expressed in adipose tissue. Its role, however, has not been fully elucidated. Here, we reveal the metabolic role of adipose-VEGF by studying mice with deletion (VEGF(AdΔ)) or doxycycline-inducible overexpression of a VEGF transgene (VEGF(AdTg)) in the adipose tissue. VEGF(AdΔ) mice have reduced adipose vascular density and show adipose hypoxia, apoptosis, inflammation, and metabolic defects on a high-fat diet. In contrast, induction of VEGF expression in VEGF(AdTg) mice leads to increased adipose vasculature and reduced hypoxia. The latter changes are sufficient to counteract an established compromising effect of high-fat diet on the metabolism, indicating that metabolic misbalance is reversible by adipose vessel density increase. Our data clearly show the essential role of VEGF signaling for adequate adipose function. Besides revealing insights into the molecular mechanisms of obesity-related metabolic diseases, this study points to the therapeutic potential of increased adipose angiogenesis.

Objective: Exosomal microRNAs (miRNAs) are potential biomarkers for obesity, in which they regulate biological processes. Bariatric surgery has health benefits for patients with obesity; however, the mechanisms of these benefits are not clear. This study attempted to identify the exosomal miRNA signature associated with obesity and how it changed after bariatric surgery. Methods: Healthy volunteers (HVs) and nondiabetic patients with obesity were prospectively enrolled in the study. The study assessed the serum exosomal miRNA profiles of HVs and patients with obesity using RNA sequencing. To evaluate the effects of bariatric surgery, the study also analyzed exosomal miRNAs in patients 6 months after surgery. Results: RNA sequencing revealed differential expression of 72 exosomal miRNAs in patients with obesity compared with HVs and differential expression of 41 miRNAs in post-versus presurgery blood. Among the differentially expressed miRNAs, the study identified nine surgery-responsive miRNAs that were highly expressed in patients before surgery compared with HVs. Biological pathway analysis of the nine miRNAs indicated that they are likely involved in WNT, neurotrophin, and insulin signaling; the insulin receptor signaling cascade; and focal adhesion. Conclusions: Patients with obesity have a distinct exosomal miRNA expression profile compared with HVs. In addition, weight loss after surgery alters the exosomal miRNA profile of patients with obesity.

Background Diabetic nephropathy (DN) is associated with high risk of cardiovascular disease and mortality. Exosomal microRNAs (miRNAs) regulate gene expression in a variety of tissues and play important roles in the pathology of various diseases. We hypothesized that the exosomal miRNA profile would differ between DN patients and patients without nephropathy. Methods We prospectively enrolled 74 participants, including healthy volunteers (HVs), diabetic patients without nephropathy, and those with DN. The serum exosomal miRNA profiles of participants were examined using RNA sequencing. Results The expression levels of 107 miRNAs differed between HVs and patients without DN, whereas the expression levels of 95 miRNAs differed between HVs and patients with DN. Among these miRNAs, we found 7 miRNAs (miR-1246, miR-642a-3p, let-7c-5p, miR-1255b-5p, let-7i-3p, miR-5010-5p, miR-150-3p) that were uniquely up-regulated in DN patients compared to HVs, and miR-4449 that was highly expressed in DN patients compared to patients without DN. A pathway analysis revealed that these eight miRNAs are likely involved in MAPK signaling, integrin function in angiogenesis, and regulation of the AP-1 transcription factor. Moreover, they were all significantly correlated with the degree of albuminuria. Conclusions Patients with DN have a different serum exosomal miRNA profile compared to HVs. These miRNAs may be promising candidates for the diagnosis and treatment of DN and cardiovascular disease. Electronic supplementary material The online version of this article (10.1186/s12967-019-1983-3) contains supplementary material, which is available to authorized users.

Senescent cells accumulate in various tissues over time, and contribute to tissue dysfunction and aging-associated phenotypes. Accumulating evidence suggests that cellular senescence can be inhibited through pharmacological intervention, as well as through treatment with soluble factors derived from embryonic stem cells (ESCs). In an attempt to investigate the anti-senescence factors secreted by ESCs, we analyzed mouse ESC-derived extracellular miRNAs in conditioned medium (CM) via miRNA array analysis. We selected mmu-miR-291a-3p as a putative anti-senescence factor via bioinformatics analysis. We validated its inhibitory effects on replicative, adriamycin-induced, and ionizing radiation-induced senescence in human dermal fibroblasts. Treatment of senescent cells with mmu-miR-291a-3p decreased senescence-associated-β-galactosidase activity, enhanced proliferative potential, and reduced mRNA and protein expression of TGFBR2, p53, and p21. Mmu-miR-291a-3p in CM was enclosed in ESC-derived exosomes and exosomes purified from ESC-CM inhibited cellular senescence. The inhibitory effects of mmu-miR-291a-3p were mediated through the TGFBR2 signaling pathway. Hsa-miR-371a-3p and hsa-miR-520e, the human homologs of mmu-miR-291a-3p, showed similar anti-senescence activity. Furthermore, mmu-miR-291a-3p accelerated the excisional skin wound healing process in aged mice. Our results indicate that the ESC-derived mmu-miR-291a-3p is a novel candidate agent that can be utilized for cell-free therapeutic intervention against aging and aging-related diseases.

IntroductionObesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease. T2DM increases the risk of cardiovascular-related death. We investigated changes in circulating exosomal microRNA (miRNA) profiles in patients with DM with obesity compared with patients without DM with obesity.Research design and methodsThis prospective study involved 29 patients with obesity (patients without DM=16, patients with DM=13) and healthy volunteers (HVs) (n=18). We measured circulating levels of exosomal miRNAs by next-generation sequencing and compared miRNA levels across the three groups.ResultsThe expression levels of 25 miRNAs (upregulated=14, downregulated=11) differed between patients with obesity with DM and patients with obesity without DM. Compared with HV, patients with DM with obesity had 53 dysregulated miRNAs. Additionally, moving stepwise from HV to patients with obesity without DM to patients with obesity with DM, there was a consistent increase in expression levels of miR-23a-5p and miR-6087 and a consistent decrease in expressions levels of miR-6751-3p.ConclusionsOur data show that the exosomal miRNAs is altered by dysregulated glucose metabolism in patients with obesity. This circulating exosomal miRNA signature in patients with obesity with or without DM is a potential biomarker and therapeutic target in these patients.