Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inflammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracellular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-α (TNF-α). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor κB (NF-κB) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-a expression, whereas NF-κB inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-κB activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-κB dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.
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Huixia Li, Zhuanmin Zhang, Dongxu Feng, Lin Xu, Fang Li, Jiali Liu, Xinxin Jin, Zhuang Qian, Xiaomin Kang, and Hongzhi Sun
Huixia Li, Hui Meng, Min Xu, Xin Gao, Xulei Sun, Xinxin Jin, and Hongzhi Sun
Bone mass declines with age and its maintenance is tightly linked to osteoblasts (crucial bone-building cells). Although disruption of the peripheral circadian clock is involved in various pathologies including aging-related diseases, evidence regarding how the peripheral clock regulates bone mass remains elusive. In the present study, we aimed to elucidate the effects of Bmal1 (the key activator of the peripheral circadian clock system) knockdown by lentivirus-mediated shRNA on osteoblast differentiation and its related mechanisms. We found that the expression of osteogenic markers, alkaline phosphatase activity, and mineralization were decreased, whereas apoptosis and inflammatory response were increased in Bmal1 knockdown osteoblasts. In addition, Bmal1 knockdown promoted ERK and JNK phosphorylation, as well as mTOR activity, whereas mTOR inhibition by rapamycin abrogated Bmal1 knockdown-mediated effects on osteoblast differentiation and mineralization capacity. Remarkably, Bmal1 knockdown in osteoblasts inhibited GSK3β/β-catenin signaling with decreased β-catenin expression and GSK-3β phosphorylation at serine 9, while GSK3β inhibition with TDZD-8, but not WNT3a or SKL2001, rescued Bmal1 knockdown-induced defects in osteoblast differentiation. Moreover, rapamycin partly nullified the suppression of Bmal1 knockdown on β-catenin expression and GSK-3β phosphorylation. Collectively, overall data indicated that circadian gene Bmal1 regulated osteoblast differentiation and inflammatory response in an mTOR/GSK3β/β-catenin-dependent manner, and thereby may contribute to the mineralization process and bone modeling/remodeling.
