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)-a, interleukin (IL)-6, IL-1b, and interferon (IFN)-g 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-a, IL-1b, and IFN-g 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 proinflammatory cytokines resulted in delipidation and reduction of lipid-laden adipocyte numbers. Despite this reduction of lipid-laden adipocytes, TNF-a, IL-6/sIL-6R, and IL-1b 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 HMWadiponectin found in insulin-resistant conditions seems unlikely. Furthermore, delipidizing adipocytes and preadipocytes are active leptin producers when stimulated by TNF-a, IL-6/sIL-6R, and IL-1b.

PCR array and protein array studies demonstrate that IL-1β(interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

“…However, the secretion of other anti-inflammatory factors, such as IL-10, was markedly stimulated by IL-1β, and thus the overall effect of IL-1β on inflammation in adipose tissue is not uni-dimensional. In contrast to adiponectin, production of leptin, the other signature hormone of adipocytes, is stimulated by IL-1β (Sarraf et al, 1997;Simons et al, 2007).…”

Association of serum omentin-1 levels with coronary artery disease

“…Pan et al [9] also reported a negative correlation between the level of serum omentin-1 and IL-6 in patients with newly diagnosed and untreated type 2 diabetes. Several groups have reported that IL-6 regulates the production of other adipokines, including leptin, adiponectin, and visfatin [32][33][34] . IL-6 and omentin are primarily produced by stromal vascular fraction cells of adipose tissue with paracrine or endocrine effects directly on other cells locally and sys- CAD, coronary artery disease; OR, odds ratio; CI, confidence interval; TC, total cholesterol; IL-6, interleukin-6.…”

The autocrine and paracrine roles of adipokines

“…Given that it suppresses expression of PPARγ in rat adipocytes (Tanaka et al, 1999), 3T3L1 and 3T3F442A adipocytes (Lagathu et al, 2003) and in human subcutaneous adipose tissue explants (Sopasakis et al, 2004), it is not surprising that IL-6 inhibits adiponectin expression and/or release (Fasshauer et al, 2003a, Sopasakis et al, 2004, Simons et al, 2007. Furthermore, IL-6 can induce PAI-1 (Rega et al, 2005), MCP-1 (Fasshauer et al, 2004), as well as its own expression and release (Fasshauer et al, 2003b, Lagathu et al, 2003.…”