Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production

作者：Lin, Ligen; Pang, Weijun; Chen, Keyun; Wang, Fei; Gengler, Jon; Sun, Yuxiang; Tong, Qiang^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2012, 302(12): E1550-E1559.

DOI：10.1152/ajpendo.00462.2011

• reactive oxygen species
• nicotinamide adenine dinucleotide phosphate oxidase
• tumor necrosis factor-alpha
• interleukin-1 beta
• c-Jun NH2-terminal kinase
• lipolysis

We have reported previously that ETS family transcription factor PU.1 is expressed in mature adipocytes of white adipose tissue. PU.1 expression is increased greatly in mouse models of genetic or diet-induced tissue. PU.1, we show that PU.1 expression is increased only in visceral but not subcutaneous adipose tissues of obese mice, and the adipocytes are responsible for this increase in PU.1 expression. To further address PU.1's physiological function in mature adipocytes, PU.1 was knocked down in 3T3-L1 cells using retroviral-mediated expression of PU.1-targeting shRNA. Consistent with previous findings that PU.1 regulates its target genes, such as NADPH oxidase subunits and proinflammatory cytokines in myeloid cells, the mRNA levels of proinflammatory cytokines (TNF alpha, IL-1 beta, and IL-6) and cytosolic components of NADPH oxidase (p47phox and p40phox) were down-regulated significantly in PU.1-silenced adipocytes. NADPH oxidase is a main source for reactive oxygen species (ROS) generation. Indeed, silencing PU.1 suppressed NADPH oxidase activity and attenuated ROS in basal or hydrogen peroxide-treated adipocytes.Silencing PU.1 in adipocytes suppressed JNK1 activation and IRS-1 phosphorylation at Ser(307). Consequently, PU.1 knockdown improved insulin signaling and increased glucose uptake in basal and insulin-stimulated conditions. Furthermore, knocking down PU.1 suppressed basal lipolysis but activated stimulated lipolysis.Collectively, these findings indicate that obesity induces PU.1 expression in adipocytes to upregulate the production of ROS and proinflammatory cytokines, both of which lead to JNK1 activation, insulin resistance, and dysregulation of lipolysis. Therefore, PU.1 might be a mediator for obesity-induced adipose inflammation and insulin resistance.

• 出版日期2012-6
• 单位西北农林科技大学