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Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue
Author(s) -
Lundh Morten,
Petersen Patricia SS,
Isidor Marie S,
KazokaSørensen Dolly NM,
Plucińska Kaja,
Shamsi Farnaz,
Ørskov Cathrine,
Tozzi Marco,
Brown Erin L,
Andersen Emil,
Ma Tao,
Müller Ulrich,
Barrès Romain,
Kristiansen Viggo B,
GerhartHines Zachary,
Tseng YuHua,
Emanuelli Brice
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948216
Subject(s) - library science , health science , medicine , family medicine , gerontology , medical education , computer science
Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine‐tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell‐autonomous and phosphorylation‐dependent manner. Insulin‐stimulated Afadin‐S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC 6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue‐specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet‐induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin‐induced cellular feedback mechanism governed by the interaction of Afadin with HDAC 6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.