title: Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity.
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.
authors.affiliation: Obesity Research Center, Section of Endocrinology, Diabetes, and Nutrition, School of Medicine, Boston University, Boston, MA 02118 School of Medicine, University of Maryland, Baltimore, MD 21201 mijlee@bu.edu.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Endocrinology, Diabetes, and Nutrition, School of Medicine, University of Maryland, Baltimore, MD 21201.
authors.forename: Rong-Ze
authors.initials: RZ
authors.lastname: Yang
authors.affiliation: Obesity Research Center, Section of Endocrinology, Diabetes, and Nutrition, School of Medicine, Boston University, Boston, MA 02118 School of Medicine, University of Maryland, Baltimore, MD 21201.
authors.forename: Kalypso
authors.initials: K
authors.lastname: Karastergiou
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32804.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: Division of Reproductive Endocrinology, School of Medicine, University of California, San Diego, San Diego, CA 92093.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Chang
authors.affiliation: Department of Endocrinology, Diabetes, and Nutrition, School of Medicine, University of Maryland, Baltimore, MD 21201.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Gong
authors.affiliation: Obesity Research Center, Section of Endocrinology, Diabetes, and Nutrition, School of Medicine, Boston University, Boston, MA 02118 School of Medicine, University of Maryland, Baltimore, MD 21201.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000328:Adult; D001706:Biopsy; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D054392:Adipokines; D015850:Interleukin-6; D020738:Leptin; D016328:NF-kappa B; C498143:RELA protein, human; D012333:RNA, Messenger; C404226:TSC22D3 protein, human; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054638:Dual Specificity Phosphatase 1
keywords: glucocorticoid-induced leucine zipper; interleukin-6; leptin; mitogen-activated protein kinase; mitogen-activated protein kinase phosphatase-1; nuclear factor κB