The low molecular weight protein tyrosine phosphatase promotes adipogenesis and subcutaneous adipocyte hypertrophy

Autor: Matthew R. Bliss, Vida Zhang, Alessia Lodi, Meghan Collins, Stephanie M. Stanford, Stefano Tiziani, Michael A. Diaz, Nunzio Bottini, Paul Gries, Zachary J. Holmes
Rok vydání: 2021
Předmět:
0301 basic medicine
Receptor
Platelet-Derived Growth Factor alpha
Physiology
Clinical Biochemistry
Peroxisome proliferator-activated receptor
Adipose tissue
Protein tyrosine phosphatase
p38 Mitogen-Activated Protein Kinases
Mice
Phosphoserine
chemistry.chemical_compound
0302 clinical medicine
Adipocyte
Adipocytes
Phosphorylation
Mice
Knockout
chemistry.chemical_classification
Adipogenesis
biology
Chemistry
Cell Differentiation
Mitochondria
Cell biology
030220 oncology & carcinogenesis
Metabolome
Glycolysis
Signal Transduction
Cell Respiration
Subcutaneous Fat
Models
Biological
Article
Electron Transport
03 medical and health sciences
3T3-L1 Cells
Proto-Oncogene Proteins
Animals
Cell Size
JNK Mitogen-Activated Protein Kinases
Hypertrophy
Cell Biology
PPAR gamma
Insulin receptor
Glucose
030104 developmental biology
Gene Expression Regulation
biology.protein
Protein Tyrosine Phosphatases
Adipocyte hypertrophy
Gene Deletion
Zdroj: J Cell Physiol
ISSN: 1097-4652
0021-9541
DOI: 10.1002/jcp.30307
Popis: Obesity is a major contributing factor to the pathogenesis of Type 2 diabetes. Multiple human genetics studies suggest that high activity of the low molecular weight protein tyrosine phosphatase (LMPTP) promotes metabolic syndrome in obesity. We reported that LMPTP is a critical promoter of insulin resistance in obesity by regulating liver insulin receptor signaling and that inhibition of LMPTP reverses obesity-associated diabetes in mice. Since LMPTP is expressed in adipose tissue but little is known about its function, here we examined the role of LMPTP in adipocyte biology. Using conditional knockout mice, we found that selective deletion of LMPTP in adipocytes impaired obesity-induced subcutaneous adipocyte hypertrophy. We assessed the role of LMPTP in adipogenesis in vitro, and found that LMPTP deletion or knockdown substantially impaired differentiation of primary preadipocytes and 3T3-L1 cells into adipocytes, respectively. Inhibition of LMPTP in 3T3-L1 preadipocytes also reduced adipogenesis and expression of proadipogenic transcription factors peroxisome proliferator activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha. Inhibition of LMPTP increased basal phosphorylation of platelet-derived growth factor receptor alpha (PDGFRα) on activation motif residue Y849 in 3T3-L1, resulting in increased activation of the mitogen-associated protein kinases p38 and c-Jun N-terminal kinase and increased PPARγ phosphorylation on inhibitory residue S82. Analysis of the metabolome of differentiating 3T3-L1 cells suggested that LMPTP inhibition decreased cell glucose utilization while enhancing mitochondrial respiration and nucleotide synthesis. In summary, we report a novel role for LMPTP as a key driver of adipocyte differentiation via control of PDGFRα signaling.
Databáze: OpenAIRE
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