期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：7
页码：1529-1534
DOI：10.1073/pnas.1720475115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Adipose tissue dysfunction is causally implicated in the impaired metabolic homeostasis associated with obesity; however, detailed mechanisms underlying dysregulated adipocyte functions in obesity remain to be elucidated. Here we searched for genes that provide a previously unknown mechanism in adipocyte metabolic functions and identified family with sequence similarity 13, member A (Fam13a) as a factor that modifies insulin signal cascade in adipocytes. Fam13a was highly expressed in adipose tissue, predominantly in mature adipocytes, and its expression was substantially reduced in adipose tissues of obese compared with lean mice. We revealed that Fam13a accentuated insulin signaling by recruiting protein phosphatase 2A with insulin receptor substrate 1 (IRS1), leading to protection of IRS1 from proteasomal degradation. We further demonstrated that genetic loss of Fam13a exacerbated obesity-related metabolic disorders, while targeted activation of Fam13a in adipocytes ameliorated it in association with altered adipose tissue insulin sensitivity in mice. Our data unveiled a previously unknown mechanism in the regulation of adipocyte insulin signaling by Fam13a and identified its significant role in systemic metabolic homeostasis, shedding light on Fam13a as a pharmacotherapeutic target to treat obesity-related metabolic disorders.
