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

Sanchez-Ceinos, J.; Guzman-Ruiz, R.; Rangel-Zuniga, O. A.; Moreno-Cano, E.; del Rio-Moreno, M.; Maymo-Masip, E.; Vendrell, J.; Fernandez-Veledo, S.; Laurencikiene, J.; Ryden, M.; Membrives, A.; Luque, R. M.; Lopez-Miranda, J.; M. Malagon, M.

doi:10.1101/2021.01.15.426823

bioRxiv · 10.1101/2021.01.15.426823

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

Sanchez-Ceinos, J.·Guzman-Ruiz, R.·Rangel-Zuniga, O. A.·Moreno-Cano, E.·del Rio-Moreno, M.·Maymo-Masip, E.·Vendrell, J.·Fernandez-Veledo, S.·Laurencikiene, J.·Ryden, M.·Membrives, A.·Luque, R. M.·Lopez-Miranda, J.·M. Malagon, M.

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Abstract

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 demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)- associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). 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 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.

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Sanchez-Ceinos, J., Guzman-Ruiz, R., Rangel-Zuniga, O. A., Moreno-Cano, E., del Rio-Moreno, M., Maymo-Masip, E., Vendrell, J., Fernandez-Veledo, S., Laurencikiene, J., Ryden, M., Membrives, A., Luque, R. M., Lopez-Miranda, J., M. Malagon, M.. 2021-01-17. Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease. https://doi.org/10.1101/2021.01.15.426823

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