title: Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma).
abstract: One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-γ (PPARγ). Here, we report that a deficiency of β-arrestin-1 expression affects PPARγ-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that β-arrestin-1 interacts with PPARγ. β-Arrestin-1 suppressed the formation of a complex between PPARγ and 9-cis-retinoic acid receptor-α through its direct interaction with PPARγ. The interaction of β-arrestin-1 with PPARγ repressed PPARγ/9-cis-retinoic acid receptor-α function but promoted PPARγ/nuclear receptor corepressor function in PPARγ-mediated adipogenesis and inflammatory gene expression. Consistent with these results, a deficiency of β-arrestin-1 binding to PPARγ abolished its suppression of PPARγ-dependent adipogenesis and inflammatory responses. These results indicate that the regulation of PPARγ by β-arrestin-1 is critical. Furthermore, in vivo expression of β-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 β-arrestin-1 but also suggest a potential tactical approach against obesity and its associated metabolic disorders.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Tongji University, Shanghai 200092, China.
authors.forename: Le-nan
authors.initials: LN
authors.lastname: Zhuang
authors.forename: Wen-xiang
authors.initials: WX
authors.lastname: Hu
authors.forename: Shun-mei
authors.initials: SM
authors.lastname: Xin
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; D019390:Arrestins; D047495:PPAR gamma; D047488:Retinoid X Receptors; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins