Sfrp5 Is an Anti-Inflammatory Adipokine That Modulates Metabolic Dysfunction in Obesity

Abstract

Adipose tissue secretes proteins referred to as adipokines, many of which promote inflammation and disrupt glucose homeostasis. Here we show that secreted frizzled-related protein 5 (Sfrp5), a protein previously linked to the Wnt signaling pathway, is an anti-inflammatory adipokine whose expression is perturbed in models of obesity and type 2 diabetes. Sfrp5-deficient mice fed a high-calorie diet developed severe glucose intolerance and hepatic steatosis, and their adipose tissue showed an accumulation of activated macrophages that was associated with activation of the c-Jun N-terminal kinase signaling pathway. Adenovirus-mediated delivery of Sfrp5 to mouse models of obesity ameliorated glucose intolerance and hepatic steatosis. Thus, in the setting of obesity, Sfrp5 secretion by adipocytes exerts salutary effects on metabolic dysfunction by controlling inflammatory cells within adipose tissue.

Obesity, inflammation, and insulin resistance

“…In obese rats, Ouchi et al (2010) observed reduced SFRP5 expression and increased Wnt-5a expression. This confirms that detectable serum levels of and SFRP5 are present in obese individuals and these bioactive peptides can be affected by level of nutrition.…”

“…Yet, obesity leads to decreased SFRP5 expression and increased Wnt-5a expression in adipocytes, activating the c-jun amino (N)-terminal kinase 1 (JNK-1) pathway and triggering a pro-inflammatory response. The activation of JNK-1 impairs the activity of a target protein called insulin receptor substrate-1 (IRS-1) leading to suppressed insulin signaling and development of insulin resistance (Oh, Olefsky, 2010;Ouchi et al, 2010).…”

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

“…There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11]. Inhibition of the acyltransferase Porcupine, which is central to posttranslational modification required for functional Wnt proteins [37], improved clearance of nonpathogenic Escherichia coli in vivo [5].…”

“…Clinical associations of elevated Wnt expression and pathway activity with infections [2,3,6] and chronic inflammatory diseases [8,9,11] have sparked significant interest in elucidating immune-related functions of Wnt signaling. There is strong experimental evidence for the contribution of endogenous Wnt proteins to inflammatory cytokine responses and host defense against pathogens in in vivo models [5,11,20] as well as in a variety of cell culture systems [2,6,13,14,36]. In a model of dietinduced metabolic dysfunction, sFRP5 exerted anti-inflammatory functions in vivo, possibly by interfering with Wnt5a-induced proinflammatory cytokine production [11].…”

“…IL-12 and IL-6) and chemokines (e.g. CCL2 and CCL5) by macrophages and other cell types [2,6,11,13,14]. Wnt proteins, such as Wnt5a, which signal via β-Catenin-independent pathways, including Ca 2+ mobilization, NF-κB, and MAP kinase activation, have been proposed to amplify local inflammation [15,16].…”