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Adipocytes function as an energy buffer and undergo significant size and volume changes in response to nutritional cues. This adipocyte plasticity is important for systemic lipid metabolism and insulin sensitivity. Accompanying the adipocyte size and volume changes, the mechanical pressure against cell membrane also changes. However, the role that mechanical pressure plays in lipid metabolism and insulin sensitivity remains to be elucidated. Here we show that Piezo1, a mechanically-activated cation channel stimulated by membrane tension and stretch, was highly expressed in adipocytes. Adipose Piezo1 expression was increased in obese mice. Adipose-specific piezo1 knockout mice (adipose-Piezo1 −/− ) developed insulin resistance, especially when challenged with a high-fat diet (HFD). Perigonadal white adipose tissue (pgWAT) weight was reduced while pro-inflammatory and lipolysis genes were increased in the pgWAT of HFD-fed adipose-Piezo1 −/− mice. The adipose-Piezo1 −/− mice also developed hepatic steatosis with elevated expression of fatty acid synthesis genes. In cultured adipocytes, Piezo1 activation decreased, while Piezo1 inhibition elevated pro-inflammatory gene expression. TLR4 antagonist TAK-242 abolished adipocyte inflammation induced by Piezo1 inhibition. Thus, adipose Piezo1 may serve as an adaptive mechanism for adipocyte plasticity restraining pro-inflammatory response in obesity.

Angiogenesis is a process of new blood vessel formation from pre-existing vessels. Vascular endothelial growth factor-A (VEGF-A) binds to VEGF receptor-2 (VEGFR2) and thus activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a central role in angiogenesis. Total flavones of Abelmoschus manihot (TFA), the major active component of the traditional Chinese herb Abelmoschus manihot, display novel pro-angiogenic activity. However, little information concerning its underlying mechanism is available. Here we investigate the pro-angiogenesis of TFA with the aim of understanding its mechanism of action. Human umbilical vein endothelial cells (HUVECs) and the chick chorioallantoic membrane (CAM) model were used to evaluate pro-angiogenesis of TFA using cell viability, wounding healing, transwell invasion, tube formation, RT-qPCR and Western blot methods. LY294002, a PI3K inhibitor, was used to interfere with PI3K/Akt pathway signal for assessing the underlying mechanism. Results in vitro indicated TFA obviously promoted HUVECs proliferation, migration, invasion and tube formation. Furthermore, TFA markedly augmented PI3K and Akt phosphorylation and up-regulated VEGF-A and VEGFR2 expression in HUVECs. However, pre-treatment with LY294002 not only markedly attenuated TFA-induced cells proliferation, migration, invasion and tube formation, but also significantly abolished TFA-induced VEGF-A and VEGFR2 over-expression as well as PI3K and Akt phosphorylation. Experiments in CAM model showed TFA significantly promoted the formation of branched blood vessels and was dramatically suppressed by LY294002. Taken together, TFA promoted angiogenesis both in vitro and in vivo which, however, were counteracted by LY294002, suggesting at least in part, TFA exhibits pro-angiogenic activity by activating the VEGF-A/VEGFR2-PI3K/Akt signaling axis.

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