Lee, Mi-Jeong, Yang, Rong-Ze, Karastergiou, Kalypso, Smith, Steven R., Chang, Jeffery R., Gong, Da-Wei, Fried, Susan K.
funding text
This work supported by a start-up fund from the Department of Medicine, Boston University School of Medicine and a Pilot and Feasibility grant from Joslin Diabetes Center (M-J.L.), National Institute of Diabetes and Digestive and Kidney Diseases Grants R01DK080448 and P30DK046200 (S.K.F.), and the Society for Women's Health Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest.
abstract
The glucocorticoid-induced leucine zipper (GILZ), a primary target of glucocorticoids, is expressed in human adipocytes, but its importance in adipocyte function is unknown. Because TNF alpha is increased in obese adipose tissue and antagonizes a number of glucocorticoid actions, we investigated the interplay of these pathways. GILZ knockdown increased and GILZ overexpression decreased interleukin-6 (IL-6) and leptin mRNA and protein secretion. GILZ knockdown increased the magnitude of the glucocorticoid effect on leptin secretion, but did not affect the glucocorticoid suppression of IL-6. Although GILZ silencing decreased adiponectin mRNA levels, it did not affect the amount of adiponectin secreted. GILZ negatively modulated pro-inflammatory signaling pathways, blocking basal and TNF alpha-stimulated (1 h) p65 nuclear factor. B nuclear translocation and transcriptional activity by binding to p65 in the cytoplasm. GILZ silencing increased basal ERK1/2 and JNK phosphorylation, and decreased MAPK phosphatase-1 protein levels. Longer term TNF alpha (4 h or 24 h) treatment decreased GILZ expression in human adipocytes. Furthermore, adipose tissue GILZ mRNA levels were reduced in proportion to the degree of obesity and expression of inflammatory markers. Overall, these results suggest that GILZ antagonizes the proinflammatory effects of TNF alpha in human adipocytes, and its downregulation in obesity may contribute to adipose inflammation and dysregulated adipokine production, and thereby systemic metabolism.-Lee, M-J., R-Z. Yang, K. Karastergiou, S. R. Smith, J. R. Chang, D-W. Gong, and S. K. Fried. Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity.