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 TNFα 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 TNFα-stimulated (1 h) p65 nuclear factor κB 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 TNFα (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 pro-inflammatory effects of TNFα in human adipocytes, and its downregulation in obesity may contribute to adipose inflammation and dysregulated adipokine production, and thereby systemic metabolism.
Highlights
The glucocorticoid-induced leucine zipper (GILZ), a primary target of glucocorticoids, is expressed in human adipocytes, but its importance in adipocyte function is unknown
We previously found that GILZ is expressed in human adipose tissue and newly differentiated human adipocytes in culture, and its expression is upregulated by dexamethasone (Dex) through glucocorticoid receptor (GR) [4, 17]
This article is available online at http://www.jlr.org been addressed. Using both loss- and gain-of-function approaches, we investigated the role of GILZ on adipokine production, focusing on interleukin-6 (IL-6) and leptin, both of which can have pro-inflammatory actions, and adiponectin, which is an anti-inflammatory and insulinsensitizing adipokine [18]
Summary
The glucocorticoid-induced leucine zipper (GILZ), a primary target of glucocorticoids, is expressed in human adipocytes, but its importance in adipocyte function is unknown. 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 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. The role of GILZ in adipocyte function, has not Abbreviations: ATGL, adipose tissue triglyceride lipase; Dex, dexamethasone; GILZ, glucocorticoid-induced leucine zipper; GR, glucocorticoid receptor; IL-6, interleukin-6; MKP-1, MAPK phosphatase-1; NF- B, nuclear factor B
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