Family with sequence similarity 13, member A modulates adipocyte insulin signaling and preserves systemic metabolic homeostasis

Abstract

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.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

“…Many previous papers reported a critical role of WAT insulin signaling in the regulation of systemic metabolic homeostasis 48,49 . Furthermore, it has been reported that enhancing insulin signaling in adipocytes is sufficient to improve systemic metabolic homeostasis, while impaired insulin signaling in adipocytes causes systemic metabolic disorders 50,51 . Therefore, adipocyte senescence induces systemic metabolic disorders at least partially through impairing fat insulin signaling.…”

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

“…Previous genome-wide association studies suggest a strong association between FAM13A and chronic lung diseases. FAM13A is expressed in various types of tissues and cells, including airway and alveolar epithelial cells in the lung, pulmonary vascular cells, and mature adipocytes in adipose tissue [10,11,24]. Accordingly, FAM13A has been involved in multiple biological processes such as epithelial cell regeneration, tumor cell proliferation and survival, and insulin signaling.…”

“…FAM13A interacts with protein phosphatase 2A and β-catenin, leading to the promotion of GSK-3β-mediated phosphorylation and subsequent proteasomal degradation of β-catenin in airway epithelial cells [10]. Interestingly, FAM13A is also expressed in adipocytes, and modulates insulin signaling through regulating the proteasomal degradation of insulin receptor substrate-1 [11].…”

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

“…FAM13A also has two coiled-coil domains that often play a role in the protein-protein interaction. Indeed, FAM13A binds to insulin receptor substrate-1 in a coiled-coil domain-dependent manner, while it binds to protein phosphatase 2A (PP2A) independently of their coiled-coil domain [11]. Other study in COPD has revealed the importance of interaction between FAM13A and PP2A in bronchial epithelial cells that leads to β-catenin degradation through GSK3β-mediated phosphorylation, although the coiled-coil domain dependency is not clear [10].…”

“…FAM13A interacts with protein phosphatase 2A and β-catenin, leading to the promotion of GSK-3β-mediated phosphorylation and subsequent proteasomal degradation of β-catenin in airway epithelial cells [10]. Interestingly, FAM13A was also expressed in adipocytes, and modulates insulin signaling through regulating the proteasomal degradation of insulin receptor substrate-1 [11].…”