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Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer
Author(s) -
Meng Guanmin,
Tang Xiaoyun,
Yang Zelei,
Zhao Yuan Yuan,
Curtis Jonathan M.,
Mcmullen Todd P. W.,
Brindley David N.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801226r
Subject(s) - autotaxin , adipose tissue , breast cancer , medicine , endocrinology , dexamethasone , cancer , oncology , receptor , lysophosphatidic acid
Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs . LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase‐2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti‐inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX–LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10–1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL‐6, TNF‐α, peroxisome proliferator‐activated receptor (PPAR)‐γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex‐induced decreases in ATX and adiponectin secretion, but did not reverse Dex‐induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex‐treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1‐phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti‐inflammatory effects of Dex through decreased signaling by the ATX‐LPA‐inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.—Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer. FASEB J. 33, 1899‐1910 (2019). www.fasebj.org