Obesity is associated with a state of chronic low-grade inflammation, which contributes to insulin resistance and type 2 diabetes. However, the molecular mechanisms that link obesity to inflammation are not fully understood. Follistatin-like 1 (FSTL1) is a novel proinflammatory cytokine that is expressed in adipose tissue and secreted by preadipocytes/adipocytes. We aimed to test whether FSTL1 could have a role in obesity-induced inflammation and insulin resistance. It was found that FSTL1 expression was markedly decreased during differentiation of 3T3-L1 preadipocytes but reinduced by TNF-α. Furthermore, a significant increase in FSTL1 levels was observed in adipose tissue of obese ob/ob mice, as well as in serum of overweight/obese subjects. Mechanistic studies revealed that FSTL1 induced inflammatory responses in both 3T3-L1 adipocytes and RAW264.7 macrophages. The expression of proinflammatory mediators including IL-6, TNF-α, and MCP-1 was upregulated by recombinant FSTL1 in a dose-dependent manner, paralleled with activation of the IKKβ-NFκB and JNK signaling pathways in the two cell lines. Moreover, FSTL1 impaired insulin signaling in 3T3-L1 adipocytes, as revealed by attenuated phosphorylation of both Akt and IRS-1 in response to insulin stimulation. Together, our results suggest that FSTL1 is a potential mediator of inflammation and insulin resistance in obesity. 1. Introduction Obesity has reached epidemic proportions worldwide and affects both adults and children [1]. Accumulating evidence indicates that obesity is associated with chronic low-grade inflammation, characterized by increased proinflammatory cytokine production and accumulation of macrophages in adipose tissue [2–4]. Initially viewed as a major site for energy storage, recently it has become evident that adipose tissue is also an important endocrine and immune organ, which secretes a variety of bioactive molecules termed as adipokines [5]. During the development of obesity, the secretory function of adipose tissue changes dramatically. Whereas the secretion of proinflammatory cytokines such as TNF- and IL-6 is increased, the production of anti-inflammatory adipokines/cytokines is reduced [6, 7]. The imbalance between pro- and anti-inflammatory mediators contributes to the chronic inflammation in obesity, which in turn leads to insulin resistance and other obesity-associated diseases [6, 7]. To date, many proinflammatory cytokines, in addition to TNF- and IL-6, have been linked to obesity-induced inflammation and insulin resistance [6–8]. Follistatin-like 1 (FSTL1) is a secreted
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