β-Arrestin-1 Protein Represses Adipogenesis and Inflammatory Responses through Its Interaction with Peroxisome Proliferator-activated Receptor-γ (PPARγ)

One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-gamma (PPAR gamma). Here, we report that a deficiency of beta-arrestin-1 expression affects PPAR gamma-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that beta-arrestin-1 interacts with PPAR gamma. beta-Arrestin-1 suppressed the formation of a complex between PPAR gamma and 9-cis-retinoic acid receptor-alpha through its direct interaction with PPAR gamma. The interaction of beta-arrestin-1 with PPAR gamma repressed PPAR gamma/9-cis-retinoic acid receptor-alpha function but promoted PPAR gamma/nuclear receptor corepressor function in PPAR gamma-mediated adipogenesis and inflammatory gene expression. Consistent with these results, a deficiency of beta-arrestin-1 binding to PPAR gamma abolished its suppression of PPAR gamma-dependent adipogenesis and inflammatory responses. These results indicate that the regulation of PPAR gamma by beta-arrestin-1 is critical. Furthermore, in vivo expression of beta-arrestin-1 (but not the binding-deficient mutant) significantly repressed adipogenesis, macrophage infiltration, and diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Therefore, our findings not only reveal a molecular mechanism for the modulation of obesity by beta-arrestin-1 but also suggest a potential tactical approach against obesity and its associated metabolic disorders.