TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β.
Montserrat RomeroAlba Sabaté-PérezVíctor A FrancisIgnacio Castrillón-RodriguezÁngels Díaz-RamosManuela Sánchez-FeutrieXavier DuránManuel PalacínJosé María Moreno-NavarreteBirgit GustafsonAnn HammarstedtJosé Manuel Fernández-RealJoan VendrellUlf SmithAntonio ZorzanoPublished in: Nature cell biology (2018)
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.
Keyphrases
- signaling pathway
- adipose tissue
- pi k akt
- insulin resistance
- cell death
- high fat diet induced
- epithelial mesenchymal transition
- endoplasmic reticulum stress
- transcription factor
- cardiovascular disease
- oxidative stress
- weight gain
- cell proliferation
- poor prognosis
- type diabetes
- body mass index
- gene expression
- skeletal muscle
- physical activity
- young adults
- genome wide identification
- bioinformatics analysis