MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN
Location: Children Nutrition Research Center (Houston, Tx)
Title: Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production
| Lin, Ligen - |
| Pang, Weijun - |
| Chen, Ke Yun - |
| Wang, Fei - |
| Gengler, Jon - |
| Sun, Yuxiang - |
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 15, 2012
Publication Date: March 27, 2012
Citation: Lin, L., Pang, W., Chen, K., Wang, F., Gengler, J., Sun, Y., Tong, Q. 2012. Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production. American Journal of Physiology - Endocrinology and Metabolism. 302:E1550-E1559.
Interpretive Summary: It is known that compared to subcutaneous fat, gaining abdominal fat is associated with a worse metabolic outcome. Obesity induces profound changes in adipose tissue, especially increases the production and release of free radicals and factors that stimulate inflammation, causing diabetes and heart diseases. We found that obesity induces an increased expression of the PU.1 gene in fat cells of the abdominal fat but not the subcutaneous fat. We further demonstrated that suppressing PU.1 expression in fat cells decreased expression of genes that are controlled by PU.1, such as pro-inflammatory factors and enzymes responsible for free radical production. Therefore, if we can find a practical way to suppress PU.1 in fat cells in obese individuals, we might be able to block the production of free radicals and inflammatory factors and decrease the chances of the development of diabetes and heart diseases in them. Such findings could have importance in obesity prevention.
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 obesity. Here, 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 (TNFalpha, IL-1beta, and IL-6) and cytosolic components of NADPH oxidase (p47phox and p40phox) were downregulated 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.