2. Academic Validation
  3. Glucose-Responsive PAGR1-Regulated Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

Glucose-Responsive PAGR1-Regulated Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

  • Adv Sci (Weinh). 2025 Jul 24:e02763. doi: 10.1002/advs.202502763.
Chenyun Ding 1,  Yuhuan Jia 1,  Lin Liu 1,  Wen Wang 2,  Danxia Zhou 1,  Zheng Zhou 1,  Likun Yang 1,  Xinyi Chen 1,  Di Chen 2,  Yan Mao 1,  Liwei Xiao 1,  Cai-Zhi Liu 3,  Zhen-Yu Du 4,  Yujing Yin 1,  Qiqi Guo 1,  Zongchao Sun 1,  Kai Ge 5,  Tingting Fu 1,  Hai-Long Piao 2,  Zhenji Gan 1
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, 210061, China.
  • 2 Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
  • 3 Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 4 LANEH, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 5 Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
PMID: 40703063 DOI: 10.1002/advs.202502763
Abstract

Chronic hyperglycemia, a defining feature of type 2 diabetes (T2D) and related metabolic disorders, exacerbates Insulin resistance and impairs muscle glucose utilization, contributing to systemic metabolic dysfunction. While skeletal muscle is the primary site for postprandial glucose uptake and plays a pivotal role in maintaining whole-body glucose homeostasis, the molecular mechanisms by which hyperglycemia induces maladaptive responses in muscle remain poorly understood. Here, PAXIP1-associated glutamate-rich protein 1 (PAGR1) is identified as a glucose-responsive regulator in skeletal muscle, whose expression is induced by high glucose levels and modulates systemic glucose homeostasis and hepatic metabolism. Using muscle-specific PAGR1-knockout mice, it is demonstrated that PAGR1 deficiency enhances Insulin signaling, promotes glucose transporter 4 (GLUT4) translocation, and increases muscle glucose uptake and utilization. Mechanistically, PAGR1 directly activates the expression of TBC1 Domain Family Member 4 (TBC1D4), a RAB GTPase Activating Protein (RabGAP) known to negatively regulate GLUT4 translocation. Importantly, muscle-specific deletion of PAGR1 protects against high-fat-diet-induced Insulin resistance and hepatic steatosis. These findings establish PAGR1 as a critical mediator of muscle glucose sensing and utilization, positioning it as a potential target for therapeutic strategies aimed at mitigating glucotoxicity and preventing metabolic diseases such as T2D.

Keywords

glucose homeostasis; hepatic metabolism; obesity; skeletal muscle.

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