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SOSTDC1 downregulation in CD4+ T cells confers protection against obesity-induced insulin resistance

Dehai Li1, Jing Zhu2, Mingyue Zhang2

  • 1Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.

Cell Reports
|April 2, 2025
PubMed

Insights

T cells secrete sclerostin domain-containing protein 1 (SOSTDC1), exacerbating obesity-induced insulin resistance by disrupting adipocyte lipid metabolism. Inhibiting SOSTDC1 offers a potential therapeutic approach for metabolic disorders.

Area of Science:

  • Immunology
  • Metabolic Disorders
  • Endocrinology

Background:

  • Adipose-resident T cells are implicated in obesity-induced insulin resistance.
  • The precise mechanisms, especially involving non-immune cytokines, are not fully understood.

Purpose of the Study:

  • To investigate the role of sclerostin domain-containing protein 1 (SOSTDC1) in T cells and its contribution to insulin resistance.
  • To elucidate the molecular mechanisms by which SOSTDC1 affects adipocyte function and glucose metabolism.

Main Methods:

  • Measurement of SOSTDC1 levels in individuals with type 2 diabetes (T2D).
  • Generation and analysis of T cell-specific Sostdc1-deficient mice.
  • Investigation of the LRP5/6-β-catenin pathway in adipocytes.
  • Assessment of T cell receptor (TCR) signaling impact on SOSTDC1 secretion.

Main Results:

  • Elevated SOSTDC1 levels in T2D patients correlated with fasting glucose and HbA1c.
  • T cell-specific Sostdc1-deficient mice showed resistance to age-induced lipid accumulation and glucose dysregulation.
  • SOSTDC1 promoted lipogenesis and inhibited lipolysis in adipocytes via the LRP5/6-β-catenin pathway.
  • TCR signaling amplified SOSTDC1 secretion from CD4+ T cells.

Conclusions:

  • T cells contribute to obesity and insulin resistance through SOSTDC1 secretion.
  • SOSTDC1 disrupts adipocyte lipid homeostasis.
  • Targeting SOSTDC1 represents a potential immunotherapeutic strategy for metabolic diseases.
Keywords:
CD4+ T cellsCP: ImmunologyCP: MetabolismSOSTDC1adipocyteadipose tissueimmune cellsimmunometabolisminsulin resistanceobesity

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