TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β

Montserrat Romero; Alba Sabaté-Pérez; Víctor A Francis; Ignacio Castrillón-Rodriguez; Ángels Díaz-Ramos; Manuela Sánchez-Feutrie; Xavier Durán; Manuel Palacín; José María Moreno-Navarrete; Birgit Gustafson; Ann Hammarstedt; José Manuel Fernández-Real; Joan Vendrell; Ulf Smith; Antonio Zorzano

doi:10.1038/s41556-018-0072-9

TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β

Nat Cell Biol. 2018 Apr;20(4):443-454. doi: 10.1038/s41556-018-0072-9. Epub 2018 Mar 28.

Authors

Montserrat Romero^{1

2

3}, Alba Sabaté-Pérez^{1

2

3}, Víctor A Francis^{1

2

3}, Ignacio Castrillón-Rodriguez^{1

2

3}, Ángels Díaz-Ramos^{1

2

3}, Manuela Sánchez-Feutrie^{1

2

3}, Xavier Durán^{3

4

5}, Manuel Palacín^{1

2

6}, José María Moreno-Navarrete^{7

8}, Birgit Gustafson⁹, Ann Hammarstedt⁹, José Manuel Fernández-Real^{7

8}, Joan Vendrell^{3

4

5}, Ulf Smith⁹, Antonio Zorzano^{10

11

12}

Affiliations

¹ Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.
² Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
³ Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
⁴ Department of Endocrinology, Hospital Joan XXIII, Rovira i Virgili University, Tarragona, Spain.
⁵ Institut d'Investigació Sanitaria Pere Virgili (IISPV), Tarragona, Spain.
⁶ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
⁷ Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Girona, Spain.
⁸ Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, Madrid, Spain.
⁹ Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain. [email protected].
¹¹ Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. [email protected].
¹² Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [email protected].

PMID: 29593329
DOI: 10.1038/s41556-018-0072-9

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.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / enzymology*
Adipocytes / pathology
Adipogenesis*
Adipose Tissue / enzymology*
Adipose Tissue / pathology
Adiposity*
Adult
Animals
Autophagy*
Endosomal Sorting Complexes Required for Transport / metabolism
Endosomes / enzymology
Female
Glycogen Synthase Kinase 3 beta / genetics
Glycogen Synthase Kinase 3 beta / metabolism*
Humans
Hyperplasia
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein Transport
Spain
Sweden
TCF Transcription Factors / genetics
TCF Transcription Factors / metabolism
Time Factors
Transcriptional Activation
Wnt Signaling Pathway
beta Catenin / genetics
beta Catenin / metabolism*

Substances

CTNNB1 protein, human
CTNNB1 protein, mouse
Endosomal Sorting Complexes Required for Transport
Nuclear Proteins
TCF Transcription Factors
TP53INP2 protein, human
beta Catenin
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse