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<p>Metabolic disorders—particularly obesity and type 2 diabetes mellitus (T2DM)—have reached pandemic proportions and represent one of the most pressing global health challenges of the 21st century. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a master regulator of lipid metabolism, insulin sensitivity, and adipocyte differentiation, making it a validated therapeutic target. However, classical thiazolidinediones (TZDs) targeting PPARγ are limited by significant adverse effects including weight gain, fluid retention, and cardiovascular risks. This review systematically examines the structure-function relationships of PPARγ and its multi-layered regulatory mechanisms in metabolic homeostasis. We particularly focus on selective PPARγ modulators (SPPARMs) that target Ser273 phosphorylation—a strategy that preserves insulin-sensitizing efficacy while circumventing TZD-associated toxicities. Notably, we provide the first comprehensive integration of the lncRNA Snhg9 into the PPARγ regulatory framework; the Snhg9-CCAR2-SIRT1-PPARγ axis represents a novel lncRNA-mediated mechanism with potential implications for RNA-based therapeutics. Finally, we propose the DNA-binding domain (DBD) as an emerging target that may enable gene-selective PPARγ modulation—a paradigm shift beyond conventional ligand-binding domain (LBD)-focused strategies. This review provides a strategic roadmap for next-generation PPARγ-targeted therapies in metabolic diseases.</p>

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Novel perspectives on PPARγ regulation: from SPPARMs to the emerging role of lncRNAs in metabolic disorders

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Hao Qin,
  • YuanYuan Wang,
  • Yukai Yang,
  • Yinhua Xiong,
  • Lingling Luo,
  • Liang Peng,
  • Lin Zhang

摘要

Metabolic disorders—particularly obesity and type 2 diabetes mellitus (T2DM)—have reached pandemic proportions and represent one of the most pressing global health challenges of the 21st century. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a master regulator of lipid metabolism, insulin sensitivity, and adipocyte differentiation, making it a validated therapeutic target. However, classical thiazolidinediones (TZDs) targeting PPARγ are limited by significant adverse effects including weight gain, fluid retention, and cardiovascular risks. This review systematically examines the structure-function relationships of PPARγ and its multi-layered regulatory mechanisms in metabolic homeostasis. We particularly focus on selective PPARγ modulators (SPPARMs) that target Ser273 phosphorylation—a strategy that preserves insulin-sensitizing efficacy while circumventing TZD-associated toxicities. Notably, we provide the first comprehensive integration of the lncRNA Snhg9 into the PPARγ regulatory framework; the Snhg9-CCAR2-SIRT1-PPARγ axis represents a novel lncRNA-mediated mechanism with potential implications for RNA-based therapeutics. Finally, we propose the DNA-binding domain (DBD) as an emerging target that may enable gene-selective PPARγ modulation—a paradigm shift beyond conventional ligand-binding domain (LBD)-focused strategies. This review provides a strategic roadmap for next-generation PPARγ-targeted therapies in metabolic diseases.