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

Shuhong Sun,Ran Wang,Jianwen Song,Ming Guan,Na Li,Xiaotian Zhang,Zhenwen Zhao,Junjie Zhang

doi:10.1194/jlr.m075655

Shuhong Sun, Ran Wang + Show 6 more

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https://doi.org/10.1194/jlr.m075655

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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.

Highlights

Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine
Coknockdown of JAK1, JAK2, JAK3, and TYK2 significantly inhibited ATX expression in adipocytes (Fig. 2C). These results suggest that JAK1/2 and TYK2 are involved in ATX expression regulation in adipocytes
These findings demonstrate that activation of the gp130-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway is required for the high level of ATX expression found in adipocytes

Summary

Introduction

Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine. Upregulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. 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. ATX expression in adipose tissue and plasma LPA levels are upregulated in high-fat diet (HFD)-fed obese mice [11]. Adipocyte-specific ATX knockout mice fed a HFD display less insulin resistance than WT mice fed the same diet [12], suggesting that ATX from adipose tissue contributes to the impaired glucose homeostasis observed in diet-induced obesity.

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