Abstract
The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.
Highlights
The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders
We have recently shown that Afadin is phosphorylated at S1795 in response to insulin via Akt[13], and found that Afadin S1795 phosphorylation was increased upon 3 h of cold exposure (Fig. 1a,d)
We show that the abundance and phosphorylation of the scaffold protein Afadin is induced by cold in BAT, and it is required for adequate adaptation to acute cold exposure
Summary
The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. We have recently discovered that the intracellular scaffold protein Afadin, encoded by the Mllt[4] gene, is a negative regulator of insulin signalling in adipose tissues[13]. In non-adipose tissues, Afadin has been shown to be a critical component of cell–cell contacts in the form of adherens junctions, and as an important regulator of cell polarization, differentiation, survival, migration and gene t ranscription[14,15], demonstrating the pleiotropic functions of this protein. Since insulin action plays an important role in BAT thermogenesis, we set out to investigate the role of Afadin in the adaptation of BAT to cold exposure. Our data uncover the role of Afadin in modulating BAT thermogenesis and physiology
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