title: Pro-inflammatory delipidizing cytokines reduce adiponectin secretion from human adipocytes without affecting adiponectin oligomerization.
abstract: Adiponectin and, especially, its oligomeric complex composition have been suggested to be critical in determining insulin sensitivity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in obesity and associated diseases. Therefore, we investigated the effect of long-term exposure of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, and interferon (IFN)-gamma on total insulin-sensitizing adiponectin secretion and adiponectin complex formation from human adipocytes. In parallel, adipocyte delipidation and leptin production levels were monitored. The present study demonstrates that TNF-alpha, IL-1beta, and IFN-gamma dose and time dependently suppressed total adiponectin secretion within 7 days (60, 70, and 35% reduction respectively). IL-6 was also able to reduce (50%) adiponectin production, although only in combination with exogenous soluble IL-6 receptors (sIL-6R). However, the oligomeric distribution (high, middle, and low molecular weight (HMW) complexes) of secreted adiponectin was not altered by any of these cytokines. All studied pro-inflammatory cytokines resulted in delipidation and reduction of lipid-laden adipocyte numbers. Despite this reduction of lipid-laden adipocytes, TNF-alpha, IL-6/sIL-6R, and IL-1beta stimulated leptin release. Our data indicate that (i) long-term pro-inflammatory cytokine exposure downregulates total adiponectin secretion from delipidizing adipocytes and (ii) pro-inflammatory cytokines are not important regulators of adipocyte-derived adiponectin oligomerization. Hence, their individual contribution to low expression of HMW adiponectin found in insulin-resistant conditions seems unlikely. Furthermore, delipidizing adipocytes and preadipocytes are active leptin producers when stimulated by TNF-alpha, IL-6/sIL-6R, and IL-1beta.
authors.affiliation: Department of Cell Biology, Bioceros BV, Yalelaan 46, 3584 CM Utrecht, The Netherlands. p.simons@bioceros.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Simons
authors.forename: Petra S
authors.initials: PS
authors.lastname: van den Pangaart
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D001391:Azo Compounds; D049109:Cell Proliferation; D002478:Cells, Cultured; D004396:Coloring Agents; D016207:Cytokines / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050151:Subcutaneous Fat; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D001391:Azo Compounds; D004396:Coloring Agents; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D020738:Leptin; D020033:Protein Isoforms; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C011049:oil red O