Pro-inflammatory delipidizing cytokines reduce adiponectin secretion from human adipocytes without affecting adiponectin oligomerization.
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.
Simons
Peter J
PJ
Department of Cell Biology, Bioceros BV, Yalelaan 46, 3584 CM Utrecht, The Netherlands. p.simons@bioceros.com
van den Pangaart
Petra S
PS
Aerts
Johannes M F G
JM
Boon
Louis
L
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
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