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.
Highlights
Chronic, low-grade inflammation in adipose tissue induced by obesity is characterized by an aberrant release of hormones, cytokines and chemokines
Several proinflammatory cytokines and chemokines such as tumor necrosis factor a (TNFa), monocyte chemotactic protein 1 (MCP-1) and chemerin, which participate in the detrimental crosstalk between adipose tissue and skeletal muscle and progression of insulin resistance during obesity, were identified [1,2,3]
Exposing adipocytes to secreted frizzled-related protein 5 (Sfrp5) prior to TNFa incubation lowered the secretion of IL-6 by 49% (p,0.05), but had no impact on the release of monocyte chemotactic protein-1 (MCP)-1 and adiponectin as compared to cells exposed to TNFa only (Figure 2A-C)
Summary
Low-grade inflammation in adipose tissue induced by obesity is characterized by an aberrant release of hormones, cytokines and chemokines. These factors affect insulin sensitivity in an auto-/paracrine fashion in adipose tissue and in an endocrine manner in liver and skeletal muscle. We recently reported a positive association of Sfrp with insulin resistance and markers of oxidative stress in mostly overweight and obese Caucasians, indicating that the function of Sfrp in humans may be dependent on the subjects’ metabolic and inflammatory state [14]
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