Regulators of TNF\u03b1 mediated insulin resistance elucidated by quantitative proteomics

Rodrigo Mohallem,Uma K. Aryal

doi:10.1038/s41598-020-77914-1

Abstract

Obesity is a growing epidemic worldwide and is a major risk factor for several chronic diseases, including diabetes, kidney disease, heart disease, and cancer. Obesity often leads to type 2 diabetes mellitus, via the increased production of proinflammatory cytokines such as tumor necrosis factor-α (TNFα). Our study combines different proteomic techniques to investigate the changes in the global proteome, secretome and phosphoproteome of adipocytes under chronic inflammation condition, as well as fundamental cross-talks between different cellular pathways regulated by chronic TNFα exposure. Our results show that many key regulator proteins of the canonical and non-canonical NF-κB pathways, such as Nfkb2, and its downstream effectors, including Csf-1 and Lgals3bp, directly involved in leukocyte migration and invasion, were significantly upregulated at the intra and extracellular proteomes suggesting the progression of inflammation. Our data provides evidence of several key proteins that play a role in the development of insulin resistance.

Highlights

Obesity is a growing epidemic worldwide and is a major risk factor for several chronic diseases, including diabetes, kidney disease, heart disease, and cancer
We identified several different proteins involved in the IFNα/β signaling pathway, including the transcription factors Signal transducer and activator of transcription 1 (Stat1) and 2 (Stat2), Interferon-inducible GTPase 1 (Iigp1), and interferon-induced protein with tetratricopeptide repeats 2 (Ifit2) and 3 (Ifit3), suggesting a potential cross-talk between the tumor necrosis factor-α (TNFα) and IFNα/β activated pathways
We unveiled the changes of the adipocyte proteome and phosphoproteome during chronic TNFα treatment, by combining time resolved global proteomic, secretomic and phosphoproteomic analysis

Summary

Introduction

Obesity is a growing epidemic worldwide and is a major risk factor for several chronic diseases, including diabetes, kidney disease, heart disease, and cancer. Obesity often leads to type 2 diabetes mellitus, via the increased production of proinflammatory cytokines such as tumor necrosis factor-α (TNFα). Increased production of pro-inflammatory adipokines, such as tumor necrosis factor-α (TNFα), interleukine-6 (IL-6), and interleukine-3 (IL-3), induces insulin resistance, either by directly disrupting the canonical insulin signaling pathway, or by stimulating the activation of additional inflammatory pathways[6]. The abnormal secretion of adipokines induces the recruitment and invasion of B cells, T cells, and subsequently macrophages to the adipose tissue. IFN-γ and IL-17 secreting T-cells stimulate the proinflammatory activation of adipocyte tissue macrophages (ATM’s). Subsequent to the activation of the NF-κB cascade, the secretion of other adipokines are further stimulated, notably monocyte chemotactic protein-1 (MCP-1), a cytokine that promotes the recruitment of leukocytes to the inflammation site[12]. Identifying the primary effectors and elucidating crosstalks between underlying molecular mechanisms involved in disrupting insulin signaling

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