Introduction and Objective: Diabetes affects 1 in 10 Americans, highlighting the urgent need for novel therapeutic targets. The insulin receptor (InsR) signaling pathway, classically defined as IRS→ PI3K→ Akt→ FoxO1, is central to glucose regulation. However, evidence suggests an alternative, IRS→Akt-independent mechanism. This study investigates whether BRD7 (bromodomain-containing protein 7) regulates glucose homeostasis via a non-canonical InsR pathway.Methods: BRD7 function in glucose metabolism was examined using mouse models and cell-based experiments. BRD7 expression was manipulated via adenoviral overexpression and knockout in WT and IRS1/2-double knockout (IRS-DKO) mice. Western blot analysis assessed phosphorylation of key signaling proteins. GTT, ITT, and PTT evaluated metabolic effects. In Akt1/2-DKO cells, BRD7-mediated phosphorylation of GSK3β, S6K, and 4E-BP1 was analyzed. Temporal activation patterns were determined in primary hepatocytes and liver tissues from WT mice after fasting-refeeding.Results: BRD7 requires InsR but bypasses IRS1/2 for glucose regulation. BRD7 phosphorylated GSK3β independently of Akt. In Akt1/2-DKO cells, BRD7 increased S6K phosphorylation but not 4E-BP1, suggesting differential protein synthesis regulation. In ob/ob mice, BRD7 overexpression reduced FoxO1 levels in a 6-hour fasted state but not during prolonged fasting, indicating a postprandial role. BRD7 improved glucose homeostasis in IRS-DKO mice by lowering fasting glucose, enhancing glucose tolerance, and reducing gluconeogenesis. Temporal analysis revealed early IRS1/2 activation upon insulin stimulation, while BRD7 phosphorylation emerged later, sustaining glucose regulation beyond 36 hours.Conclusion: BRD7 regulates glucose metabolism via a non-canonical InsR pathway independent of IRS→Akt, particularly in postprandial states. These findings highlight BRD7 as a potential therapeutic target for diabetes.
S. Park: None.
R01DK118244
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