PMID- 24661543 OWN - NLM STAT- MEDLINE DCOM- 20140715 LR - 20140519 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 63 IP - 6 DP - 2014 Jun TI - TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. PG - 812-21 LID - S0026-0495(14)00054-7 [pii] LID - 10.1016/j.metabol.2014.02.015 [doi] AB - OBJECTIVE: Adipose tissue is an extra-thyroidal thyroid-stimulating hormone (TSH) target. Increases in lipolysis and in expression and release of interleukin-6 (IL-6) occur in TSH-stimulated adipocytes, and levels of circulating free fatty acids and IL-6 rise following TSH administration to patients with previous thyroidectomy and radioablation for thyroid cancer. Our first objective was to compare how TSH stimulates protein kinase A (PKA) and inhibitor of kappaB (IkappaB) kinase (IKK)-beta. Our second objective was to investigate whether TSH induces other cytokines besides IL-6. METHODS: TSH stimulation of either CHO cells expressing human TSH receptor or human abdominal subcutaneous differentiated adipocytes. RESULTS: Signaling studies showed TSH increased NADPH oxidase activity, and either diphenyleneiodonium (oxidase inhibitor) or N-acetyl cysteine (scavenger of reactive oxygen species) reduced IKKbeta phosphorylation. Phosphorylation of protein kinase C-delta, an upstream regulator of NADPH oxidase, was increased by TSH, and rottlerin (PKCdelta inhibitor) reduced TSH-stimulated IKKbeta phosphorylation. TSH upregulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the release of MCP-1 protein in human abdominal differentiated adipocytes. H89 (PKA inhibitor) and sc-514 (IKKbeta inhibitor) each blocked TSH-stimulated MCP-1 mRNA expression and protein release, suggesting PKA and IKKbeta participate in this pathway. CONCLUSIONS: These data provide new information about TSH signaling in human differentiated adipocytes, and add to the evidence that TSH is a pro-inflammatory stimulus of adipocytes. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Gagnon, AnneMarie AU - Gagnon A AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. FAU - Langille, Melanie L AU - Langille ML AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. FAU - Chaker, Seham AU - Chaker S AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. FAU - Antunes, Tayze T AU - Antunes TT AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. FAU - Durand, Jason AU - Durand J AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. FAU - Sorisky, Alexander AU - Sorisky A AD - Chronic Disease Program, Ottawa Hospital Research Institute, Departments of Medicine and of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: asorisky@ohri.ca. LA - eng GR - MOP-102585/Canadian Institutes of Health Research/Canada PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140302 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Interleukin-6) RN - 0 (RNA, Messenger) RN - 9002-71-5 (Thyrotropin) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - EC 2.7.11.10 (IKBKB protein, human) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Adipocytes/*metabolism MH - Adult MH - Animals MH - CHO Cells MH - Cell Differentiation MH - Chemokine CCL2/genetics/*metabolism MH - Cricetinae MH - Cricetulus MH - Cyclic AMP-Dependent Protein Kinases/drug effects/*metabolism MH - Female MH - Gene Expression Regulation MH - Humans MH - I-kappa B Kinase/antagonists & inhibitors/*metabolism MH - Interleukin-6/*metabolism MH - Lipolysis/drug effects MH - Male MH - Middle Aged MH - Phosphorylation MH - RNA, Messenger/metabolism MH - Signal Transduction/drug effects MH - Subcutaneous Fat, Abdominal/*cytology MH - Thyrotropin/*metabolism/pharmacology OTO - NOTNLM OT - Inhibitor of kappaB kinase-beta OT - Monocyte chemoattractant protein-1 OT - NADPH oxidase OT - Protein kinase C-delta OT - Thyroid-stimulating hormone EDAT- 2014/03/26 06:00 MHDA- 2014/07/16 06:00 CRDT- 2014/03/26 06:00 PHST- 2013/11/11 00:00 [received] PHST- 2014/02/25 00:00 [revised] PHST- 2014/02/25 00:00 [accepted] PHST- 2014/03/26 06:00 [entrez] PHST- 2014/03/26 06:00 [pubmed] PHST- 2014/07/16 06:00 [medline] AID - S0026-0495(14)00054-7 [pii] AID - 10.1016/j.metabol.2014.02.015 [doi] PST - ppublish SO - Metabolism. 2014 Jun;63(6):812-21. doi: 10.1016/j.metabol.2014.02.015. Epub 2014 Mar 2.