Blocking gp130 signaling suppresses autotaxin expression in adipocytes and improves insulin sensitivity in diet-induced obesity

Abstract

Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine. Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Upregulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that glycoprotein 130 (gp130)-mediated Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) activation was required for abundant ATX expression in adipocytes. Through gp130, the interleukin 6 (IL-6) family cytokines, such as IL-6, leukemia inhibitory factor, cardiotrophin-1, and ciliary neurotrophic factor, upregulated ATX expression in adipocytes. ATX contributes to the induction of insulin resistance and lipolysis in IL-6-stimulated adipocytes. Oral administration of gp130 inhibitor SC144 suppressed ATX expression in adipose tissue, decreased plasma ATX, LPA, and FFA levels, and significantly improved insulin sensitivity and glucose tolerance in high-fat diet-fed obese mice. In summary, our results indicate that the activation of gp130-JAK-STAT3 pathway by IL-6 family cytokines has an important role in regulating ATX expression in adipocytes and that gp130 is a promising target in the management of obesity-associated glucose metabolic diseases.

Autotaxin/lysophosphatidic acid signaling mediates obesity‐related cardiomyopathy in mice and human subjects

“…insulin resistance-inducing factors, including interleukin-6 (IL-6), glucose and insulin, induce the expression and secretion of autotaxin in inflammatory status. 15 Consistently, the mRNA expression of fat autotaxin is significantly increased of both dietary and genetic obese mice, which is accompanied by increased circulating level of LPA. 16 LPA has numerous effects in almost all cell types through its G protein-coupled receptors, which plays a decisive role in the development of several diseases.…”

“…Furthermore, circulating levels of autotaxin correlate positively with insulin resistance in older humans, and are an independent predictor for non‐alcoholic fatty liver disease . Several insulin resistance‐inducing factors, including interleukin‐6 (IL‐6), glucose and insulin, induce the expression and secretion of autotaxin in inflammatory status . Consistently, the mRNA expression of fat autotaxin is significantly increased of both dietary and genetic obese mice, which is accompanied by increased circulating level of LPA .…”

Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

“…Fifth, we could not investigate the relationship between CMV infection and possible transcriptional factors for ATX. Several transcriptional factors have been implicated for ATX up-regulation in other cells, including c-Jun and STAT3 (signal transducer and activator of transcription 3) [50][51][52] . We would like to further explore molecular basis for the CMV induced autotaxin upregulation in the trabecular meshwork cells in the future study.…”

Latest advances in STAT signaling and function in adipocytes

“…In contrast with EPO-induced STAT3 activation, which improved measures of insulin sensitivity, signaling through the glycoprotein 130 (gp130)-JAK-STAT3 axis is associated with insulin resistance in vitro and in vivo [37]. As shown in Figure 2, gp130, a plasma membrane signaling receptor, is required for the action of many JAK-STAT cytokines and hormones.…”