ArticleThe Journal of biological chemistry2015
Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Association of the stress hyperglycemia ratio for all-cause and cardiovascular mortality in population with cardiovascular-kidney-metabolic syndrome stages 0-4: evidence from a large cohort study.Diabetology & metabolic syndrome · 2025Article
- Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6.Journal of cachexia, sarcopenia and muscle · 2024Article
- Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance.Diabetes & metabolism journal · 2024Review
- Antioxidant effects of LEDT in dystrophic muscle cells: involvement of PGC-1α and UCP-3 pathways.Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2024Article
- Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases.International journal of molecular sciences · 2023Review
- Insulin resistance in cardiovascular disease, uremia, and peritoneal dialysis.Trends in endocrinology and metabolism: TEM · 2021Review
- Insulin signaling in the heart.American journal of physiology. Endocrinology and metabolism · 2021Review
- KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy.Circulation research · 2021Article
- Dietary Fat and Sugar Differentially Affect β-Adrenergic Stimulation of Cardiac ERK and AKT Pathways in C57BL/6 Male Mice Subjected to High-Calorie Feeding.The Journal of nutrition · 2020Article
- Article
- Important Trends in UCP3 Investigation.Frontiers in physiology · 2019Review
- Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion.Basic research in cardiology · 2018Article
- Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling.Antioxidants & redox signaling · 2018Review
- Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders.Nature communications · 2018Article
- Temporal partitioning of adaptive responses of the murine heart to fasting.Life sciences · 2018Article
- Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart.Trends in endocrinology and metabolism: TEM · 2017Review
- Glucose regulates the intrinsic inflammatory response of the heart to surgically induced hypothermic ischemic arrest and reperfusion.Physiological genomics · 2017Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The risk for heart failure and death after myocardial infarction is abnormally high in diabetic subjects. We and others have shown previously that mitochondrial uncoupling protein 3 (UCP3) improves functional recovery of the rodent heart during reperfusion. Here, we demonstrate that pharmacological induction of hyperinsulinemia in mice down-regulates myocardial UCP3. Decreased UCP3 expression was linked to the development of selective insulin resistance in the heart, characterized by decreased basal activity of Akt but preserved activity of the p44/42 mitogen-activated protein kinase, and overactivation of the sterol regulatory element-binding protein (SREBP)-1-mediated lipogenic program. In cultured myocytes, insulin treatment and SREBP-1 overexpression decreased, whereas SREBP-1 interference increased, peroxisome proliferator-activated receptor-stimulated expression of UCP3. Promoter deletion and site-directed mutagenesis identified three functional sterol regulatory elements in the vicinity of a known complex intronic enhancer. Increased binding of SREBP-1 to this DNA region was confirmed in the heart of hyperinsulinemic mice. In conclusion, we describe a hitherto unknown regulatory mechanism by which insulin inhibits cardiac UCP3 expression through activation of the lipogenic factor SREBP-1. Sustained down-regulation of cardiac UCP3 by hyperinsulinemia may partly explain the poor prognosis of type 2 diabetic patients after myocardial infarction.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.