Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis

Abstract

Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response resulting from the dysregulation of a wide range of insulin-controlled cellular processes. However, how insulin affects cellular energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates insulin resistance remains to be elucidated. Herein we reveal that insulin directly enhances the activity of the nuclear receptor ERRα via a GSK3β/FBXW7 signaling axis. Liver-specific deletion of GSK3β or FBXW7 and mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to fluctuating insulin levels. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in compromised energy homeostasis and reduced insulin sensitivity despite improved mitochondrial function. This crossroad of insulin signaling and transcriptional control by a nuclear receptor offers a framework to better understand the complex cellular processes contributing to the development of insulin resistance.

Innately expressed estrogen‐related receptors in the skeletal muscle are indispensable for exercise fitness

“…Our findings highlighting the impact of ERRs on muscle function should propel new studies on how ERRs are regulated. In this context, studies in other cellular systems already suggest regulation of ERRs through phosphorylation, acetylation, o‐glycosylation, and ubiquitination 34,54–57 . In turn, ERRs are likely downstream transcriptional mediators of AMPK and PGC1α, 11,14,28,58,59 two master regulators of muscle homeostasis.…”

“…In this context, studies in other cellular systems already suggest regulation of ERRs through phosphorylation, acetylation, oglycosylation, and ubiquitination. 34,[54][55][56][57] In turn, ERRs are likely downstream transcriptional mediators of AMPK and PGC1α, 11,14,28,58,59 two master regulators of muscle homeostasis. The ERRα and ERRγ muscle-specific DKO mice reported here would be a valuable tool to examine the role of ERRs downstream of the two master-regulators in a physiological setting.…”

Targeting PI3K/AKT signaling pathway in obesity

“…Downstream signals of PI3K are mediated by multiple serine/threonine (Ser/Thr) kinases, including phosphoinositide-dependent protein kinase 1 (PDK1), AKT, mammalian target of rapamycin complex (mTORC), protein kinase C (PKC), ribosomal protein S6 kinase (S6K), AKT substrate of 160 kDa (AS160) and glycogen synthase kinase 3 (GSK3), which regulate the activity of various transcriptional factors, such as Forkhead box protein O1 (FOXO1), peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1 alpha (PGC1α), and sterol regulatory element-binding proteins (SREBPs). These promote the metabolic actions of insulin on glucose, lipid, and mitochondrial metabolism, as well as effects on cell proliferation, differentiation, growth and apoptosis [30][31][32][33][34][35][36][37].…”

“…For example, treatment of murine adipocytes with tumor necrosis factor alpha (TNF-α) inhibits insulin signaling at the level of IRS1 [82] thereby inhibiting PI3K activity further downstream [83]. In turn, blocking of inflammatory mediators protects against IR in mouse models [37,84,85]. However, PI3K are not only crucial in mediating insulin response in adipose tissue, but are involved in recruitment of inflammatory cells as well, as PI3K are activated by cytokine and chemokine receptors in immune cells [23,86].…”

A new machine learning based computational framework identifies therapeutic targets and unveils influential genes in pancreatic islet cells

“…As carbohydrates break down into glucose and enter the blood stream, beta cells secrete insulin to absorb glucose into cells for energy. Insulin mainly aims to store excess glucose in the liver [4][5][6]. When beta cells do not function properly, insulin is not secreted and blood glucose levels are elevated.…”