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Updated: Oct 3, 2025

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Suppression of RIP1 activity via S415 dephosphorylation ameliorates obesity-related hepatic insulin resistance

Yanping Wang1, Jie Xiong1, Yanmei Yuan1

  • 1Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Obesity (Silver Spring, Md.)
|February 14, 2022
PubMed
Abstract

Insights

Receptor-interacting serine/threonine-protein kinase 1 (RIP1) activity increases with obesity-induced insulin resistance. Inhibiting RIP1, specifically at the novel S415 site, improves insulin sensitivity, suggesting RIP1 as a therapeutic target for type 2 diabetes.

Area of Science:

  • Molecular biology
  • Metabolic diseases
  • Cellular signaling

Background:

  • Receptor-interacting serine/threonine-protein kinase 1 (RIP1) regulates inflammation and cell death pathways implicated in obesity-related metabolic diseases.
  • The precise role of RIP1 in obesity-related insulin resistance is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which RIP1 influences insulin resistance in obesity.
  • To identify specific RIP1 modifications contributing to insulin resistance.

Main Methods:

  • Primary hepatocytes were treated with palmitic acid and necrostatin 1 or RIP1 expression.
  • Liquid chromatography-tandem mass spectrometry identified RIP1 phosphorylation sites.
  • RIP1 mutants were used to pinpoint the S415 residue's role in insulin resistance.
  • Diet-induced obese mice received adenovirus expressing a RIP1 S415A mutant to assess insulin sensitivity.

Main Results:

  • Obesity-induced insulin resistance is associated with increased RIP1 activity.
  • Inhibition of RIP1 with necrostatin 1 ameliorated hepatic insulin resistance.
  • The novel phosphorylation site S415 on RIP1 was identified as critical for mediating insulin resistance.
  • A loss-of-function mutation at S415 effectively reduced RIP1-induced insulin resistance in cellular and animal models.

Conclusions:

  • RIP1, particularly its S415 phosphorylation site, plays a significant role in the development of insulin resistance.
  • Targeting RIP1 S415 presents a potential therapeutic strategy for type 2 diabetes and related metabolic disorders.

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