Effect of Sfrp5 on Cytokine Release and Insulin Action in Primary Human Adipocytes and Skeletal Muscle Cells

Abstract

Secreted frizzled-related protein 5 (Sfrp5) is an adipokine with anti-inflammatory and insulin-sensitizing properties in mice. However, the mechanism of Sfrp5 action, especially in humans, is largely unknown. Therefore, cytokine release and insulin signaling were analyzed to investigate the impact of Sfrp5 on inflammation and insulin signaling in primary human adipocytes and skeletal muscle cells (hSkMC). Sfrp5 neither affected interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and adiponectin release from human adipocytes, nor IL-6 and IL-8 release from hSkMC. In tumor necrosis factor (TNF) α-treated adipocytes, Sfrp5 reduced IL-6 release by 49% (p<0.05), but did not affect MCP-1 and adiponectin release. In MCP-1-treated hSkMC, Sfrp5 did not affect cytokine secretion. In untreated adipocytes, Sfrp5 decreased the insulin-mediated phosphorylation of Akt-Ser473, Akt-Thr308, GSK3α-Ser21 and PRAS40-Thr246 by 34% (p<0.01), 31% (p<0.05), 37% (p<0.05) and 34% (p<0.01), respectively, and the stimulation of glucose uptake by 25% (p<0.05). Incubation with TNFα increased the phosphorylation of JNK and NFκB, and impaired insulin signaling. When Sfrp5 and TNFα were combined, there was no additional effect on insulin signaling and JNK phosphorylation, but phosphorylation of NFκB was reversed to basal levels. Sfrp5 had no effect on insulin signaling in untreated or in MCP-1 treated hSkMC. Thus, Sfrp5 lowered IL-6 release and NFκB phosphorylation in cytokine-treated human adipocytes, but not under normal conditions, and decreased insulin signaling in untreated human adipocytes. Sfrp5 did not act on hSkMC. Therefore, the cellular actions of Sfrp5 seem to depend on the type of tissue as well as its inflammatory and metabolic state.

Sfrp5 associates with beta‐cell function in humans

“…However, our results are in line with a former analysis reporting a positive association between serum Sfrp5 and HOMA-IR in overweight individuals [21]. This would be supported by our mechanistic study using primary human adipocytes which showed an inhibitory role of Sfrp5 on insulin signalling [18]. Furthermore, Sfrp5 decreased insulin-stimulated glucose uptake by 25% in human adipocytes [18].…”

Angiotensin II increases secreted frizzled-related protein 5 (sFRP5) expression through AT1 receptor/Rho/ROCK1/JNK signaling in cardiomyocytes

“…Studies focusing on the expression and molecular mechanism of sFRP5 action in cardiac hypertrophy are limited. Carstensen et al [15] demonstrated that sFRP5 reduced IL-6 release from TNF-atreated adipocytes but did not act on hSkMC and suggested that sFRP5 is tissue-specific and dependent on the metabolic and inflammatory state of the target tissue. One study reports that in vivo models of heart failure sFRP 1-4 were expressed in healthy ventricular myocardium, but sFRP3 and sFRP4 increased by 2-3-fold [8].…”

SFRP5 acts as a mature adipocyte marker but not as a regulator in adipogenesis

“…Among SFRPs, SFRP5 may interact with both canonical and non-canonical WNT signalling pathways , Satoh et al 2008 and might be an import metabolic regulator (Ouchi et al 2010, Mori et al 2012, Carstensen et al 2014. Results from an in vitro study indicated that SFRP5 impairs insulin signalling under normal conditions, but reduces tumour necrosis factor a-induced inflammation in primary human adipocytes (Carstensen et al 2014). In murine mature adipocytes, SFRP5 expression is downregulated in druginduced IR and upregulated by insulin sensitisers (Lv et al 2012).…”

“…SFRPs prevent downstream WNT signalling by binding to and sequestering WNT ligands in the extracellular space (Bovolenta et al 2008). Among SFRPs, SFRP5 may interact with both canonical and non-canonical WNT signalling pathways , Satoh et al 2008 and might be an import metabolic regulator (Ouchi et al 2010, Mori et al 2012, Carstensen et al 2014. Results from an in vitro study indicated that SFRP5 impairs insulin signalling under normal conditions, but reduces tumour necrosis factor a-induced inflammation in primary human adipocytes (Carstensen et al 2014).…”