Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease

eLife

José Manuel Fernández-Real¹  José López-Miranda²  Oriol Alberto Rangel-Zúñiga²  Mercedes Del Río-Moreno³  Raul M Luque³  Elsa Maymo-Masip⁴  Joan Vendrell⁴  Sonia Fernández-Veledo⁴  Elena Moreno-Caño⁵  Jaime López-Alcalá⁶  María M Malagón⁶  Julia Sánchez-Ceinos⁶  Rocío Guzmán-Ruiz⁶  Jurga Laurencikiene⁷  Mikael Rydén⁷  Pablo Pérez-Martínez⁸  Juan Luis Romero-Cabrera⁸  Antonio Membrives⁹ 

[1] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain;Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, and Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain;Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain;OncObesity and Metabolism Group. Department of Cell Biology, Physiology and Immunology, IMIBIC/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain;CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain;Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgil, Tarragona, Spain;Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain;Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain;Lipid Laboratory. Department of Medicine Huddinge/Karolinska Institute (KI)/Karolinska University Hospital, Stockholm, Sweden;Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain;Unidad de Gestión Clínica de Cirugía General y Digestivo, Sección de Obesidad, Reina Sofia University Hospital, Córdoba, Spain;

关键词: preadipocytes;    obesity-related metabolic diseases;    RNA splicing;    ER-proteostasis;    UPR;    ERAD;    Human;   

DOI  :  10.7554/eLife.65996

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we aimed at identifying the pathogenic processes underlying impaired adipocyte differentiation in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). We report that down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (ERAD) hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.

【 授权许可】

CC BY