Between adipose tissue and skeletal muscle and progression of insulin resistance during obesity, were identified. In contrast, the knowledge about anti-inflammatory cytokines remains limited. Currently, only adiponectin and omentin have been linked to improved insulin sensitivity and are downregulated in obesity and type 2 diabetes. Recent studies in mice also suggest an anti-inflammatory and anti-diabetic function for secreted frizzled-related protein 5. Sfrp5 antagonizes wingless-type MMTV integration site family member 5a in the non-canonical Wnt-signaling pathway. Importantly, Sfrp5-deficiency in mice results in deterioration of high-calorie diet-induced glucose intolerance, hepatic steatosis and macrophage infiltration in adipose tissue. Conversely, acute administration of Sfrp5 to obese and diabetic mice improved glucose tolerance and adipose tissue Ganoderic-acid-F inflammation. However, one report demonstrated decreased mRNA levels of Sfrp5, whereas others reported increased Sfrp5 expression in obese mice. Also studies in humans on Sfrp5 yielded conflicting results. In Chinese subjects, both reductions and increases in circulating Sfrp5 levels between obese and T2D patients Evodiamine versus control participants were reported, while no differences were observed between lean and obese Caucasian subjects. Furthermore, Sfrp5 gene expression in adipose tissue was unaffected by obesity. We recently reported a positive association of Sfrp5 with insulin resistance and markers of oxidative stress in mostly overweight and obese Caucasians, indicating that the function of Sfrp5 in humans may be dependent on the subjects’ metabolic and inflammatory state. Therefore, the aim of this study was to elucidate the mechanism of Sfrp5 action in primary human adipocytes and skeletal muscle cells by assessing the impact of Sfrp5 on insulin signaling and release of inflammatory proteins under basal culture conditions and following inflammation-induced insulin resistance. The present study shows that Sfrp5 impairs insulin signaling in adipocytes under basal culture conditions. Furthermore, Sfrp5 reduced IL-6 release from TNFa-treated adipocytes. In contrast to adipocytes, Sfrp5 did not act on hSkMC. This suggests that the cellular function of Sfrp5 is tissue-specific and dependent on the metabolic and inflammatory state of the target tissue. Studies toward the mechanism of Sfrp5 action in tissues critical for metabolic control are limited and have yielded conflicting results. Several studies reported the induction of Sfrp5 gene expression during differentiation of 3T3-L1 adipocytes and in rodent models of genetic and/or diet-induced obesity and propose a role for Sfrp5 in the adipocyte growth via suppression of the Wnt pathway and inhibition of adipocyte mitochondrial metabolism. However, the observed inhibition of IL-6 release and NFkB phosphorylation from TNFa-treated human adipocytes by recombinant Sfrp5 in the present study suggests a protective function for Sfrp5. Interestingly, inhibition of the NFkB signaling pathway was found to prevent the release of IL-6 from human adipose tissue. This protective function for Sfrp5 also fits to the reduction of transcript levels of inflammatory cytokines, including IL-6, observed in adipose tissue from insulin-resistant ob/ob, but not wild-type mice, following adenovirus-mediated Sfrp5 expression. Furthermore, a study on Asian subjects with 89 normal glucose tolerant and 87 subjects with T2D found a negative association between plasma levels of Sfrp5 and IL-6. Unfortunately, this study did not mention whether this relation was different between controls and subjects with T2D. A study with a smaller, mostly overweight or obese Caucasian population reported no association between circulating Sfrp5 and IL-6 levels.