Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

Abstract

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 HDAC6 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 HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.

Cold-induction of afadin in brown fat supports its thermogenic capacity

“…2 f). In accordance with our previous study 13 , these data show that adipogenesis was not affected by repression of Afadin. Interestingly, there was a twofold increased expression of Mllt4 –the gene encoding Afadin- upon differentiation (Fig.…”

“…1 a,c), presumably driven by cold-mediated lipolysis in white adipose tissue stimulating insulin secretion 10 . We have recently shown that Afadin is phosphorylated at S1795 in response to insulin via Akt 13 , and found that Afadin S1795 phosphorylation was also increased upon 3 h of cold exposure (Fig. 1 a,d).…”

“…We have recently discovered that the intracellular scaffold protein Afadin, encoded by the Mllt4 gene, is a negative regulator of insulin signalling in adipose tissues 13 . Insulin-stimulated phosphorylation of Afadin at S1795 allows its docking with the histone deacetylase (HDAC)-6, to promote downregulation of insulin receptor levels, associated with impaired insulin signalling and lipogenesis.…”

Insulin-induced serine 22 phosphorylation of retinoid X receptor alpha is dispensable for adipogenesis in brown adipocytes

“…Ten 9-11-week-old male C57BL/6 J mice were fasted for 4 h and anaesthetized, followed by retro-orbital injection of 1 unit insulin/saline for 5 min (5 mice per group). For the fasting/refeeding challenge, 9-week old male mice were fasted overnight, refed for either 2 or 6 h (6 mice per group), and euthanized [27]. For the high-fat diet challenge, 6-week old male mice were fed with either control diet (D12450B, Research Diets, Inc., USA) or high-fat diet (D12492, Research Diets, Inc., USA) for 8 weeks.…”

HDAC6‐mediated α‐tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy

“…HDACs belong to a family of enzymes that deacetylate acetylated proteins, consequently influencing cellular physiological process 11 . Emerging evidence suggests that HDACs involves in the development of diabetes 12 and DN 11 . Selective inhibition of HDACs, such as HDAC2, HDAC4, HDAC7 or HDAC9, improves apoptosis, autophagy, inflammation, excessive accumulation of ECM and renal fibrosis in DN 7,11,13 .…”