1. TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β.
- Author
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Romero M, Sabaté-Pérez A, Francis VA, Castrillón-Rodriguez I, Díaz-Ramos Á, Sánchez-Feutrie M, Durán X, Palacín M, Moreno-Navarrete JM, Gustafson B, Hammarstedt A, Fernández-Real JM, Vendrell J, Smith U, and Zorzano A
- Subjects
- 3T3-L1 Cells, Adipocytes pathology, Adipose Tissue pathology, Adult, Animals, Endosomal Sorting Complexes Required for Transport metabolism, Endosomes enzymology, Female, Glycogen Synthase Kinase 3 beta genetics, Humans, Hyperplasia, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Nuclear Proteins genetics, Protein Transport, Spain, Sweden, TCF Transcription Factors genetics, TCF Transcription Factors metabolism, Time Factors, Transcriptional Activation, Wnt Signaling Pathway, beta Catenin genetics, Adipocytes enzymology, Adipogenesis, Adipose Tissue enzymology, Adiposity, Autophagy, Glycogen Synthase Kinase 3 beta metabolism, Nuclear Proteins metabolism, beta Catenin metabolism
- Abstract
Excessive fat accumulation is a major risk factor for the development of type 2 diabetes mellitus and other common conditions, including cardiovascular disease and certain types of cancer. Here, we identify a mechanism that regulates adiposity based on the activator of autophagy TP53INP2. We report that TP53INP2 is a negative regulator of adipogenesis in human and mouse preadipocytes. In keeping with this, TP53INP2 ablation in mice caused enhanced adiposity, which was characterized by greater cellularity of subcutaneous adipose tissue and increased expression of master adipogenic genes. TP53INP2 modulates adipogenesis through autophagy-dependent sequestration of GSK3β into late endosomes. GSK3β sequestration was also dependent on ESCRT activity. As a result, TP53INP2 promotes greater β-catenin levels and induces the transcriptional activity of TCF/LEF transcription factors. These results demonstrate a link between autophagy, sequestration of GSK3β into late endosomes and inhibition of adipogenesis in vivo.
- Published
- 2018
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