Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor ␥ coactivator-1␣ (PGC-1␣), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.In mammals, blood glucose levels are maintained within a relatively tight range through regulation of glucose uptake by peripheral tissues and glucose secretion by the liver, protecting the body from hypoglycemia during fasting conditions and from hyperglycemia after a high-carbohydrate meal (1). In the insulin resistance state, insulin signaling is impaired, leading to dysregulation of both hepatic glucose production and glucose uptake in peripheral tissues. Abnormal elevation of hepatic glucose production contributes to fasting hyperglycemia in diabetes (2). Therefore, efforts to uncover the molecular mechanism that control hepatic gluconeogenesis are crucial to develop new therapeutic strategies.The expression of key gluconeogenic genes, including PEPCK 2 and G6PC, is controlled by hormones at the transcriptional level (3). Hormonal and nutrient regulation of hepatic glucose production primarily occurs through modulation of a complex network of transcriptional factors and cofactors, including FOXO1, cAMP response element-binding protein, cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) and PGC-1␣ (1, 4 -7). The FOXO transcription factors have emerged as important targets of insulin and growth factor action. They play a central role in cell growth, differentiation, metabolism, and stress response (8). FOXO1 contains highly conserved AKT phosphorylation sites (Thr-24, Ser-253, and Ser-316) and its activity is regulated by AKT-mediated phosphorylation of these sites. Phosphorylated FOXO1 is excluded from the nucleus, thereby decreasing its transcriptional activity (9). In normal mice, the decreased blood insulin levels during fasting promote FOXO1 nuclear localization, where it collaborates with PGC-1␣ to increase the expression of the key gluconeogenic enzymes PEPCK and G6PC (7). FOXO1 stimulates the expression of PEPCK and G6PC via direct binding to insulin respon...
Sophoricoside, which is an isoflavone glycoside found in many plant species, has recently attracted attention because of its anti-fertility activity. One solvent-free form, two solvatomorphs and an amorphous phase of sophoricoside are reported for the first time. X-ray diffractometry, differential scanning calorimetry, thermal gravimetric analysis and Fourier-transform infrared spectroscopy were used to characterize the different forms. The results show that factors such as crystal symmetry, intermolecular arrangement, conformational flexibility, hydrogen-bonding interactions and solvent incorporation lead to different solid-state forms. An investigation of the transformations of the four forms showed that they can interconvert with each other under certain conditions. Amorphous phase and solvatomorphism were unstable but can improve the solubility of sophoricoside in water.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.