ArticleProceedings of the National Academy of Sciences of the United States of America2021
An integrative transcriptional logic model of hepatic insulin resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.Science advances · 2026Article
- RNA-independent cis-autoregulatory circuits within bidirectional gene pairs control metabolism.Science advances · 2026Article
- Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.Nature communications · 2025Article
- Concerted Actions of FoxO1 and PPARα in Hepatic Gene Expression and Metabolic Adaptation.Diabetes · 2025Article
- Insulin resistance in type 2 diabetes mellitus.Nature reviews. Endocrinology · 2025Review
- DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis.Nucleic acids research · 2025Article
- TOX4 Inhibition in Chronic Hyperglycemia: Effects on Glycation Stress, Hepatic Protection, Epigenetic Mechanisms, Signaling Pathways, and Beta Cell Dynamics.Current drug metabolism · 2025Review
- Diabetes treatment by conversion of gut epithelial cells to insulin-producing cells.Journal of diabetes investigation · 2024Review
- Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.Nature communications · 2024Article
- Activation of the insulin receptor by an insulin mimetic peptide.Nature communications · 2022Article
- The FoxOs are in the ApoM house.The Journal of clinical investigation · 2022Article
- Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway.The Journal of clinical investigation · 2022Article
- TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver.Cell metabolism · 2022Article
- FOXO1 Is Present in Stomach Epithelium and Determines Gastric Cell Distribution.Gastro hep advances · 2022Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a "spreading" of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.
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