scholarly journals Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

2021 ◽  
Author(s):  
Maria da Luz Sousa Fialho ◽  
Ujang Purnama ◽  
Kaitlyn MJH Dennis ◽  
Claudia N Montes Aparicio ◽  
Marcos Castro-Guarda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Adaptation To Hypoxia ◽  
Metabolic Dysfunction ◽  
Hypoxic Response ◽  
Human Cardiomyocytes

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. <br><p>In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. <br>In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart. </p> <p></p>

scholarly journals Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

2021 ◽  
Author(s):  
Maria da Luz Sousa Fialho ◽  
Ujang Purnama ◽  
Kaitlyn MJH Dennis ◽  
Claudia N Montes Aparicio ◽  
Marcos Castro-Guarda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Adaptation To Hypoxia ◽  
Metabolic Dysfunction ◽  
Hypoxic Response ◽  
Human Cardiomyocytes

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. <br><p>In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. <br>In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart. </p> <p></p>

Abstract 14197: C14a Mutation Abolishes Mg53-Aggravated Glucose Metabolic Dysfunction and Exerts a Dominant Therapeutic Target for Ischemia and Reperfusion (i/r) Injury in Diabetic Heart

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Han Feng ◽  
Hao Shen ◽  
Matthew J Robeson ◽  
Hongkun Wu ◽  
Gengjia Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Ischemia Reperfusion ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Metabolic Dysfunction ◽  
Protective Function ◽  
Promising Target

Introduction: MG53, essential for cardiac ischemic protection, negatively regulates insulin receptor (IR) to trigger globular metabolic dysfunction, which makes up a big obstacle for its clinical use. In vitro evidence shows that C14A site of MG53 might be a promising target both to abolish MG53 regulation on IR and to keep as much protective function. However, in vivo effect on C14A mutation of MG53 is urgent to be explored. Results: Here, we found C14A knock-in mice exerted relieved insulin resistance, blood glucose, and metabolic phenotype in high fat diet-induced pre-diabetic model. C14A mutation did NOT lessen the protective effect of MG53 by either intracellular knock-in or extracellular addition of mutant protein against ischemia/reperfusion(I/R) injury in db/+ mice. Consistent with our previous study, we found that administration of MG53 on diabetic mice showed aggravated blood glucose, insulin resistance, and unstable cardiac function to induce a higher risk under I/R attack. C14A mutation reduced the affinity between IR ECD and MG53 to block recombinant human (rh) MG53-WT-triggered acute hyperglycemia, increased heart infarct area and death rate on db/db mice during I/R injury. Post-conditioning of rhMG53-C14A stabilized intra-operative blood glucose and showed stronger anti-I/R ability than MG53-WT protein on db/db mice. Conclusions: C14A mutation is a potential target for MG53 treatment on diabetic heart. This potential therapeutic approach for the treatment of patients within type 2 diabetes provides a strategy of gene engineering optimizing well-known target to draw on advantages and avoid pitfalls.

scholarly journals TXNIP regulates myocardial fatty acid oxidation via miR-33a signaling

2016 ◽  
Vol 311 (1) ◽  
pp. H64-H75 ◽  
Author(s):  
Junqin Chen ◽  
Martin E. Young ◽  
John C. Chatham ◽  
David K. Crossman ◽  
Louis J. Dell'Italia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Homeostasis ◽  
Target Genes ◽  
Contractile Function ◽  
Regulatory Element ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Myocardial Fatty Acid ◽  
Human Cardiomyocytes ◽  
Perfusion Studies

Myocardial fatty acid β-oxidation is critical for the maintenance of energy homeostasis and contractile function in the heart, but its regulation is still not fully understood. While thioredoxin-interacting protein (TXNIP) has recently been implicated in cardiac metabolism and mitochondrial function, its effects on β-oxidation have remained unexplored. Using a new cardiomyocyte-specific TXNIP knockout mouse and working heart perfusion studies, as well as loss- and gain-of-function experiments in rat H9C2 and human AC16 cardiomyocytes, we discovered that TXNIP deficiency promotes myocardial β-oxidation via signaling through a specific microRNA, miR-33a. TXNIP deficiency leads to increased binding of nuclear factor Y (NFYA) to the sterol regulatory element binding protein 2 (SREBP2) promoter, resulting in transcriptional inhibition of SREBP2 and its intronic miR-33a. This allows for increased translation of the miR-33a target genes and β-oxidation-promoting enzymes, carnitine octanoyl transferase (CROT), carnitine palmitoyl transferase 1 (CPT1), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase-β (HADHB), and AMPKα and is associated with an increase in phospho-AMPKα and phosphorylation/inactivation of acetyl-CoA-carboxylase. Thus, we have identified a novel TXNIP-NFYA-SREBP2/miR-33a-AMPKα/CROT/CPT1/HADHB pathway that is conserved in mouse, rat, and human cardiomyocytes and regulates myocardial β-oxidation.

MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness

2006 ◽  
Vol 291 (2) ◽  
pp. E298-E305 ◽  
Author(s):  
Chul-Hee Kim ◽  
Patricia Pennisi ◽  
Hong Zhao ◽  
Shoshana Yakar ◽  
Jeanne B. Kaufman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dominant Negative ◽  
Metabolic Phenotype ◽  
Dominant Negative Mutant ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Normal Expression

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 μg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.

scholarly journals Wheat Flour, Enriched with γ-Oryzanol, Phytosterol, and Ferulic Acid, Alleviates Lipid and Glucose Metabolism in High-Fat-Fructose-Fed Rats

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1697
Author(s):  
Xiao-Xuan Guo ◽  
Zhu Zeng ◽  
Yong-Zhong Qian ◽  
Jing Qiu ◽  
Kai Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Western Blot ◽  
Ferulic Acid ◽  
Wheat Flour ◽  
Lipid Accumulation ◽  
Functional Food ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Hepatic Lipid Accumulation

(1) Background: Modern dietary patterns with a high intake of fat and fructose, as well as refined carbohydrates, closely relate to lipid/glucose metabolic disorders. The main objective of this study is to provide new thoughts in designing functional food with some lipid/glucose metabolism regulating effects for obese people. (2) Methods: The alleviating abilities of γ-oryzanol, phytosterol or ferulic acid-enriched wheat flour on lipid/glucose metabolic dysfunction were evaluated in male SD rats induced by a high-fat-fructose diet. The underlying mechanisms were clarified using western blot. (3) Results: In an in vitro cell model, γ-oryzanol, phytosterol and ferulic acid regulate lipid/glucose metabolism by increasing the phosphorylation of AMPK and Akt, and PI3K expression, as well as decreasing expressions of DGAT1 and SCD. The in vivo study shows that ferulic acid and γ-oryzanol-enriched flours are beneficial for managing body weight, improving glucose metabolism, hyperlipidemia and hepatic lipid accumulation. Phytosterol-enriched flour exerted remarkable effects in regulating hyperinsulinemia, insulin resistance and hyperuricemia. Western blot analysis of proteins from liver samples reveals that these enriched flours alleviated hepatic lipid accumulation and insulin resistance through their elevation in the phosphorylation of AMPK and Akt. (4) Conclusions: Our study indicates that these enriched flours can serve as a health-promoting functional food to regulate obesity-related lipid/glucose metabolic dysfunction in rats.

scholarly journals PO-029 Advances in research on hypoxia-mediated miRNAs affecting glucose metabolism

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Han Jiang
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Theoretical Basis ◽  
Target Genes ◽  
Exercise Intervention ◽  
Stable State ◽  
Glucose Metabolism Disorders ◽  
Insulin Synthesis ◽  
Glycolipid Metabolism

Objective This article reviews the role of miRNAs in promoting insulin sensitivity, controlling insulin synthesis, and regulating insulin resistance in hypoxia exercise, and discusses the relationship between miRNAs and glucose metabolism, and the mechanism of hypoxia-induced regulation of miRNAs in glucose metabolism. It provides a theoretical basis for better research on the prevention and treatment of disorders of glucose metabolism. Methods This paper uses the literature data method, collects a large number of documents and cites more than 90 articles for comprehensive statistical analysis to write this article, which provides researchers with relevant research directions. Results Studies have shown that miRNAs such as miR-138, miR-26b, miR-27a, miR-122, miR-802 and miR-143 have regulatory effects on obesity; some miRNAs such as miR-128, miR-7, miR-25, miR -92a, miR-375 and miR-15 family (miR-15a and miR-15b) and other miRNAs play an important role in regulating glycolipid metabolism, thereby maintaining a stable state of glycolipid metabolism. Expressions such as miR-802 and miR-143 are up-regulated in the liver of obese patients, resulting in impaired glucose tolerance. Conclusions By regulating the expression of target genes and maintaining the homeostasis of glucose metabolism, miRNAs can effectively improve or prevent obesity and disorders of glucose metabolism such as type 2 diabetes. Current studies have shown that miRNAs affect glucose metabolism from insulin sensitivity, insulin synthesis and insulin resistance. At the same time, studies have shown that exercise intervention can effectively improve glucose metabolism. However, the research on the metabolism of miRNAs in glucose metabolism during hypoxia is still insufficient. It is for further study. Studying the mechanism of the effects of miRNAs on glucose metabolism in hypoxic exercise can not only provide a theoretical basis for scientific hypoglycemic and weight control, but also can be used as an intervention for the prevention and control of diseases related to glucose metabolism disorders. In the future, drugs can regulate the expression of miRNAs, thereby providing a new therapeutic approach for the treatment of diseases caused by abnormal glucose and lipid metabolism.

scholarly journals Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation

2013 ◽  
Vol 124 (8) ◽  
pp. 491-507 ◽  
Author(s):  
Silvia Bijland ◽  
Sarah J. Mancini ◽  
Ian P. Salt
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Protein Kinase ◽  
Caloric Intake ◽  
Whole Body ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Nutrient Metabolism ◽  
Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions.

scholarly journals Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance

Endocrinology ◽  
2017 ◽  
Vol 158 (9) ◽  
pp. 2988-3003 ◽  
Author(s):  
Danalea V Skarra ◽  
Angelina Hernández-Carretero ◽  
Alissa J Rivera ◽  
Arya R Anvar ◽  
Varykina G Thackray
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Polycystic Ovary ◽  
Metabolic Phenotype ◽  
Metabolic Dysfunction ◽  
Polycystic Ovaries ◽  
Female Mice ◽  
Increased Risk ◽  
Letrozole Treatment ◽  
Glucose Stimulated Insulin Secretion

Abstract Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females.

scholarly journals Short-term thermoneutral housing alters glucose metabolism and markers of adipose tissue browning in response to a high-fat diet in lean mice

2018 ◽  
Vol 315 (4) ◽  
pp. R627-R637 ◽  
Author(s):  
Zachary S. Clayton ◽  
Carrie E. McCurdy
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Phenotype ◽  
High Fat ◽  
Short Term ◽  
Housing Temperature

Systemic insulin resistance and glucose intolerance occur with as little as 3 days of a high-fat diet (HFD) in mice and humans; the mechanisms that initiate acute insulin resistance are unknown. Most laboratories house mice at 22°C, which is below their thermoneutral temperature (~30°C). Cold stress has been shown to increase white adipose tissue (WAT) browning, alter lipid trafficking, and impair immune function, whereas energy intake and expenditure decrease with increasing ambient temperature; importantly, dysregulation of these parameters has been strongly linked to obesity-induced insulin resistance. Therefore, we compared acute changes in glucose metabolism and the metabolic phenotype in lean mice in response to a control diet or HFD housed at standard vivarium (22°C) and thermoneutral (30°C) temperatures. Glucose intolerance occurred following 1 or 5 days of HFD and was independent of housing temperature or adiposity; however, the reduction in tissue-specific glucose clearance with HFD diverged by temperature with reduced brown adipose tissue (BAT) glucose uptake at 22°C but reduced soleus glucose uptake at 30°C. Fasting glucose, food intake, and energy expenditure were significantly lower at 30°C, independent of diet. Additionally, markers of browning in both BAT and inguinal subcutaneous WAT, but not perigonadal epididymal WAT, decreased at 30°C. Together, we find housing temperature has a significant impact on the cellular pathways that regulate glucose tolerance in response to an acute HFD exposure. Thus, even short-term changes in housing temperature should be highly considered in interpretation of metabolic studies in mice.

scholarly journals Modeling the Transcriptional Regulatory Network That Controls the Early Hypoxic Response in Candida albicans

2014 ◽  
Vol 13 (5) ◽  
pp. 675-690 ◽  
Author(s):  
Adnane Sellam ◽  
Marco van het Hoog ◽  
Faiza Tebbji ◽  
Cécile Beaurepaire ◽  
Malcolm Whiteway ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Gene Set Enrichment Analysis ◽  
Adaptation To Hypoxia ◽  
Gene Promoters ◽  
Transcriptional Responses ◽  
Hypoxic Response ◽  
Transcriptional Profiles

ABSTRACTWe determined the changes in transcriptional profiles that occur in the first hour following the transfer ofCandida albicansto hypoxic growth conditions. The impressive speed of this response is not compatible with current models of fungal adaptation to hypoxia that depend on the depletion of sterol and heme. Functional analysis using Gene Set Enrichment Analysis (GSEA) identified the Sit4 phosphatase, Ccr4 mRNA deacetylase, and Sko1 transcription factor (TF) as potential regulators of the early hypoxic response. Cells mutated in these and other regulators exhibit a delay in their transcriptional responses to hypoxia. Promoter occupancy data for 29 TFs were combined with the transcriptional profiles of 3,111in vivotarget genes in a Network Component Analysis (NCA) to produce a model of the dynamic and highly interconnected TF network that controls this process. With data from the TF network obtained from a variety of sources, we generated an edge and node model that was capable of separating many of the hypoxia-upregulated and -downregulated genes. Upregulated genes are centered on Tye7, Upc2, and Mrr1, which are associated with many of the gene promoters that exhibit the strongest activations. The connectivity of the model illustrates the high redundancy of this response system and the challenges that lie in determining the individual contributions of specific TFs. Finally, treating cells with an inhibitor of the oxidative phosphorylation chain mimics most of the early hypoxic profile, which suggests that this response may be initiated by a drop in ATP production.

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