Dynamic interplay between Afadin S1795 phosphorylation and diet regulates glucose homeostasis in obese mice

Autor: Kaja Plucinska, Brice Emanuelli, Marie S. Isidor, Jonas T. Treebak, Patricia S.S. Petersen, Marco Tozzi, Thomas Nielsen, Morten Lundh, Erin L. Brown, Marina Agueda-Oyarzabal, Lewin Small
Rok vydání: 2021
Předmět:
Zdroj: Tozzi, M, Brown, E L, Petersen, P SS, Lundh, M, Isidor, M S, Plucińska, K, Nielsen, T S, Agueda-Oyarzabal, M, Small, L, Treebak, J T & Emanuelli, B 2022, ' Dynamic interplay between Afadin S1795 phosphorylation and diet regulates glucose homeostasis in obese mice ', The Journal of Physiology, vol. 600, no. 4, pp. 885-902 . https://doi.org/10.1113/JP281657
ISSN: 1469-7793
0022-3751
DOI: 10.1113/jp281657
Popis: Key points Afadin is a ubiquitously expressed scaffold protein with a recently discovered role in insulin signaling and glucose metabolism. Insulin-stimulated phosphorylation of Afadin at S1795 occurs in insulin-responsive tissues such as adipose tissue, muscle, liver, pancreas and heart. Afadin abundance and AfadinS1795 phosphorylation are dynamically regulated in metabolic tissues during diet-induced obesity progression. Genetic silencing of AfadinS1795 phosphorylation improves glucose homeostasis in the early stages of diet-induced metabolic dysregulation. AfadinS1795 phosphorylation contributes to the early development of obesity-related complications in mice. Abstract Obesity is associated with systemic insulin resistance and numerous metabolic disorders. Yet, the mechanisms underlying impaired insulin action during obesity remain to be fully elucidated. Afadin is a multifunctional scaffold protein with the ability to modulate insulin action through its phosphorylation at S1795 in adipocytes. In the present study, we report that insulin-stimulated AfadinS1795 phosphorylation is not restricted to adipose tissues, but is a common signaling event in insulin-responsive tissues including muscle, liver, pancreas and heart. Furthermore, a dynamic regulation of Afadin abundance occurred during diet-induced obesity progression, while its phosphorylation was progressively attenuated. To investigate the role of AfadinS1795 phosphorylation in the regulation of whole-body metabolic homeostasis, we generated a phospho-defective mouse model (Afadin SA) in which the Afadin phosphorylation site was silenced (S1795A) at the whole-body level using CRISPR-Cas9 mediated gene-editing. Metabolic characterization of these mice under basal physiological conditions or during high fat diet (HFD) challenge revealed that preventing AfadinS1795 phosphorylation improved insulin sensitivity and glucose tolerance and increased liver glycogen storage in the early stage of diet-induced metabolic dysregulation, without affecting body weight. Taken together, our findings reveal that AfadinS1795 phosphorylation in metabolic tissues is critical during obesity progression and contributes to promote systemic insulin resistance and glucose intolerance in the early phase of diet-induced obesity. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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