The Crucial Role of Renal FOXO1 in Gluconeogenesis During Starvation and Its Implications in Kidney Disease
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ABSTRACT:
PROVIDER: PRJNA1244905 | ENA |
REPOSITORIES: ENA
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Project description:Renal gluconeogenesis accounts for a substantial fraction of systemic glucose production during starvation, yet its regulation and pathological disruption in chronic kidney disease (CKD) remain poorly understood. Here, we investigated the mechanisms governing renal gluconeogenesis during starvation and their impairment in CKD. Integrated transcriptome analysis of starved mouse kidneys revealed that starvation robustly induces gluconeogenic gene expression in proximal tubular epithelial cells through activation of FOXO1. Consistently, tubule-specific deletion of FOXO1 (FOXO1^flox/flox^; Ksp-Cre) markedly reduced renal gluconeogenic enzyme expression and resulted in hypoglycemia during starvation, establishing FOXO1 as a critical regulator of renal glucose production. In multiple CKD models, basal serum glucose levels were preserved despite suppressed renal FOXO1 activation and gluconeogenic gene expression, indicating compensatory glucose production under fed conditions. In contrast, during prolonged starvation, CKD mice developed profound hypoglycemia accompanied by impaired FOXO1 activation and insufficient induction of renal gluconeogenesis, a phenotype that was similarly observed in aged mice. In human CKD kidneys, a senescent tubular cell state was associated with coordinated downregulation of gluconeogenesis-related genes. These findings were recapitulated in cisplatin-induced senescence models, which showed diminished FOXO1 activity, reduced gluconeogenic gene expression, and decreased glucose production. Collectively, these findings identify tubular cell senescence as a pathogenic mechanism that disrupts FOXO1-dependent renal gluconeogenesis, thereby compromising glucose homeostasis during starvation in CKD and aging. Targeting tubular senescence or restoring FOXO1 signaling may represent therapeutic strategies to prevent starvation-induced hypoglycemia in these conditions.
2025-06-30 | GSE293540 | GEO
Project description:Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinase, is associated with metabolic syndrome. However, the molecular mechanisms involved remain elusive. In this study, we demonstrate that Dyrk1b expression is induced in liver by fasting and in diabetic mice. Using both in vivo and in vitro studies, we show that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT mediated FOXO1 phosphorylation at Thr24 and Ser256, thereby enhancing its nuclear retention. DYRK1B mediated phosphorylation enhances the expression of gluconeogenic genes and promotes gluconeogenesis. Further, a pharmacological inhibitor of DYRK1B significantly reduced blood glucose levels in diabetic mice. Collectively, these findings offer new insights into DYRK1B’s role in the glucose metabolism and identify it as a new therapeutic target for treating diabetes.
2025-05-07 | PXD052214 | Pride
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE262106 | GEO
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE263028 | GEO
Project description:DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis
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Project description:DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis
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Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1
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Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1 [ChIP-seq]
| PRJNA951644 | ENA
Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1 [RNA-seq]
| PRJNA951645 | ENA
Project description:The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.
2024-11-14 | PXD051593 | Pride