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Asprosin (ASP) is a recently identified adipokine secreted by white adipose tissue (WAT). It plays important roles in the maintenance of glucose homeostasis in the fasting state and in the occurrence and development of obesity. However, there is no report on whether and how ASP would inhibit angiogenesis and fat browning in the mouse adipose microenvironment. Therefore, the study sought to investigate the effects of ASP -knockout on angiogenesis and fat browning, and to identify the interaction between them in the ASP-knockout mouse adipose microenvironment. In the experiments in vivo, the ASP -knockout alleviated the obesity induced by a high fat diet (HFD) and increased the expressions of the browning-related proteins including uncoupling protein 1 (UCP1), PRD1-BF-1-RIZ1 homologus domain-containing protein-16 (PRDM16) and PPAR gamma coactivator 1 (PGC1-α) and the endothelial cell marker (CD31). In the experiments in vitro, treatment with the conditional medium (CM) from ASP -knockout adipocytes ( ASP -/- -CM) significantly promoted the proliferation, migration and angiogenesis of vascular endothelial cells, and increased the expressions of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/endothelial nitric oxide synthase (eNOS) pathway proteins. In addition, the treatment with CM from endothelial cells (EC-CM) markedly reduced the accumulation of lipid droplets and increased the expressions of the browning-related proteins and the mitochondrial contents. Moreover, the treatment with EC-CM significantly improved the energy metabolism in 3T3-L1 adipocytes. These results highlight that ASP -knockout can promote the browning and angiogenesis of WAT, and the fat browning and angiogenesis can interact in the mouse adipose microenvironment, which contributes to weight loss in the mice with obesity.

Endothelial cell injury in vascular arterial walls plays a crucial role in the pathological process of atherosclerosis. Pterostilbene, a stilbenoid chemically related to resveratrol, has anti-inflammatory, anti-apoptosis and antioxidant properties. However, the underlying mechanisms mediated by pterostilbene in regards to endothelial cell injury in vascular arterial walls are not fully understood. The purpose of the present study was to investigate the benefits of pterostilbene in a rat model of atherosclerosis. The possible mechanism of pterostilbene was also analyzed in regards to endothelial cell injury in vascular arterial walls in vitro. A rat model of atherosclerosis was established using endothelial injury of the iliac arteries. CCK-8 assay, TUNEL, immunofluorescence, western blot analysis and hematoxylin and eosin (H&E) staining were used to analyze the role of pterostilbene in the pathological processes of atherosclerosis. In vivo results showed that pterostilbene decreased cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) in plasma and attenuated interleukin (IL)-1, tumor necrosis factor (TNF)-α and IL-6 and oxidative stress injury in serum in the experimental animals. Pterostilbene treatment reduced atherogenesis, aortic plaques, macrophage infiltration and apoptosis of vascular arterial walls in the atherosclerosis rat model. In vitro assay demonstrated that pterostilbene administration increased viability of the endothelial cells, attenuated oxidative stress injury and apoptosis of endothelial cells. The results found that pterostilbene regulated endothelial cell apoptosis via the Nrf2-mediated TLR-4/MyD88/NF-κB pathway. In conclusion, data from the present study revealed that pterostilbene protects rats against atherosclerosis by regulation of the Nrf2-mediated TLR-4/MyD88/NF-κB pathway. [ABSTRACT FROM AUTHOR]

PPARγ1 and FOXO1 are the key transcription factors that regulate insulin sensitivity. We previously found that a small ubiquitin-related modifier of PPARγ1 at K77 (SUMOylation) favored endothelial insulin resistance (IR) induced by high fat/high glucose (HF/HG) administration. However, whether and how the crosstalk between SUMOylated PPARγ1 and FOXO1 would mediate the development of the endothelial IR and dysfunction remains unclear. Here, we emphasize how PPARγ1-K77 SUMOylation would interact with FOXO1 and participate in the development of the endothelial IR and dysfunction. Our results show that the combination of HF/HG and PPARγ1-K77 SUMOylation exhibits a synergistic deteriorative effect on the endothelial IR and dysfunction, presenting decreased NO levels and elevated ET-1 levels, weakened PI3K/Akt/eNOS signaling, and impaired endothelium-dependent vasodilation function. The further researches reveal that PPARγ1-K77 SUMOylation readily interacts with FOXO1, and FOXO1 occupies the PPAR response element (PPRE) which is supposed to be occupied by PPARγ, thus resulting in the decrease of PPARγ1 transcription activity and the mitigation of the PI3K/Akt signaling. Moreover, the mitigation of the PI3K/Akt signaling promotes in turn the accumulation of FOXO1 in the nucleus where FOXO1 interacts with the SUMOylated PPARγ1, thus exerting a positive feedback effect on IR pathogenesis. The findings uncover a novel association between PPARγ1-K77 SUMOylation and FOXO1, which contributes to our understanding of the pathogenesis of endothelial IR and dysfunction and provides novel pharmacological targets for diabetic angiopathy. [Display omitted] • PPARγ1-K77 SUMOylation combined with HF/HG exhibits a synergistic deteriorative effect on the endothelial IR and dysfunction. • PPARγ1-K77 SUMOylation impairs rats endothelium-dependent vasodilation. • FOXO1 blocks the PPRE binding site on PI3K and represses the PPARγ transcription activity via PPARγ1-K77 SUMOylation. • PPARγ1-K77 SUMOylation causes FOXO1 nuclear accumulation by negatively regulating FOXO1 phosphorylation via PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

As a flavonoid, naringin (Nar) has been shown to have multiple pharmacological effects including lowering blood cholesterol, reducing thrombus formation and improving microcirculation. However, effects of Nar on function and autophagy of vascular endothelial cells under high glucose and high fat (HG/HF) stress are largely unclear. This study was designed to investigate such effects of Nar in human umbilical vein endothelial cells (HUVECs) and to determine whether such effects are related to autophagy. Our present results show that 86 μM of Nar inhibits the autophagy levels and protects the cells against the dysfunction induced by HG/HF stress. Moreover, Nar increases the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and mammalian rapamycin target protein (mTOR). However, pretreatment with rapamycin (RAPA, 5 μM, autophagy inducer), LY294002(10 μM, PI3K inhibitor) and Akt inhibitor Ⅳ (0.5 μM, Akt inhibitor) partially abrogates the protective effects of Nar, suggesting that the protective effects of Nar are achieved by activating the PI3K-Akt-mTOR pathway to inhibit autophagy. In conclusion, Nar improves the function of HUVECs under HG/HF stress through activating the PI3K-Akt-mTOR pathway to inhibit autophagy. The findings offer an insight into HG/HF stress-induced autophagy and indicate that Nar might have potential to prevent and treat the diabetic angiopathy. Image 1 [ABSTRACT FROM AUTHOR]