FoxO integration of insulin signaling with glucose and lipid metabolism

The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA-binding domain, known as ‘forkhead box’ domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here, we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.

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The Role of Peroxisome Proliferator-Activated Receptor γ in Mediating Cardioprotection Against Ischemia/Reperfusion Injury

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248417707049 ◽

2017 ◽

Vol 23 (1) ◽

pp. 46-56 ◽

Cited By ~ 9

Author(s):

Chong-Bin Zhong ◽

Xi Chen ◽

Xu-Yue Zhou ◽

Xian-Bao Wang

Keyword(s):

Lipid Metabolism ◽

Target Genes ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose And Lipid Metabolism ◽

Cardioprotective Effects

Myocardial infarction (MI) is a serious cardiovascular disease resulting in high rates of morbidity and mortality. Although advances have been made in restoring myocardial perfusion in ischemic areas, decreases in cardiomyocyte death and infarct size are still limited, attributing to myocardial ischemia/reperfusion (I/R) injury. It is necessary to develop therapies to restrict myocardial I/R injury and protect cardiomyocytes against further damage after MI. Many studies have suggested that peroxisome proliferator-activated receptor γ (PPARγ), a ligand-inducible nuclear receptor that predominantly regulates glucose and lipid metabolism, is a promising therapeutic target for ameliorating myocardial I/R injury. Thus, this review focuses on the role of PPARγ in cardioprotection during myocardial I/R. The cardioprotective effects of PPARγ, including attenuating oxidative stress, inhibiting inflammatory responses, improving glucose and lipid metabolism, and antagonizing apoptosis, are described. Additionally, the underlying mechanisms of cardioprotective effects of PPARγ, such as regulating the expression of target genes, influencing other transcription factors, and modulating kinase signaling pathways, are further discussed.

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The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽

10.3390/cells10051078 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1078

Author(s):

Debasish Roy ◽

Andrea Tedeschi

Keyword(s):

Nervous System ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

Axon Regeneration ◽

Axon Growth ◽

The Body ◽

Cns Repair ◽

Cord Injury ◽

Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

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Role of ectopic olfactory receptors in glucose and lipid metabolism

British Journal of Pharmacology ◽

10.1111/bph.15666 ◽

2021 ◽

Author(s):

Siyu Zhang ◽

Linghuan Li ◽

Hanbing Li

Keyword(s):

Lipid Metabolism ◽

Olfactory Receptors ◽

Glucose And Lipid Metabolism

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Recent advances in understanding the role of FOXO3

F1000Research ◽

10.12688/f1000research.15258.1 ◽

2018 ◽

Vol 7 ◽

pp. 1372 ◽

Cited By ~ 18

Author(s):

Renae J. Stefanetti ◽

Sarah Voisin ◽

Aaron Russell ◽

Séverine Lamon

Keyword(s):

Cell Cycle ◽

Skeletal Muscle ◽

Protein Turnover ◽

Genetic Basis ◽

The Body ◽

Biological Processes ◽

Forkhead Box ◽

Protein Pool

The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.

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Resveratrol

Emerging Applications, Perspectives, and Discoveries in Cardiovascular Research - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-5225-2092-4.ch016 ◽

2017 ◽

pp. 288-308 ◽

Cited By ~ 1

Author(s):

Catherine A. Powell ◽

Jian Zhang ◽

John D. Bowman ◽

Mahua Choudhury

Keyword(s):

Histone Deacetylases ◽

Target Genes ◽

Therapeutic Option ◽

Genetic Regulation ◽

The Body ◽

Class Iii ◽

Beneficial Effects ◽

Epigenetic Regulator ◽

Cardioprotective Effects ◽

Genetic Makeup

Cardiovascular disease (CVD) is the leading cause of death in both men and women and has largely been attributed to genetic makeup and lifestyle factors. However, genetic regulation does not fully explain the pathophysiology. Recently, epigenetic regulation, the regulation of the genetic code by modifications that affect the transcription and translation of target genes, has been shown to be important. Silent information regulator-2 proteins or sirtuins are an epigenetic regulator family of class III histone deacetylases (HDACs), unique in their dependency on coenzyme NAD+, that are postulated to mediate the beneficial effects of calorie restriction, thus promoting longevity by reducing the incidence of chronic diseases such as cancer, diabetes, and CVD. Emerging evidence shows that SIRT1 is ubiquitously expressed throughout the body. Resveratrol, a plant polyphenol, has cardioprotective effects and its mechanism of action is attributed to regulation of SIRT1. Incoproation of resveratrol into the diet may be a powerful therapeutic option for the prevention and treatment of CVD.

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Uncarboxylated osteocalcin ameliorates hepatic glucose and lipid metabolism in KKAy mice via activating insulin signaling pathway

Acta Pharmacologica Sinica ◽

10.1038/s41401-019-0311-z ◽

2019 ◽

Vol 41 (3) ◽

pp. 383-393 ◽

Cited By ~ 3

Author(s):

Xiao-lin Zhang ◽

Ya-nan Wang ◽

Lu-yao Ma ◽

Zhong-sheng Liu ◽

Fei Ye ◽

...

Keyword(s):

Lipid Metabolism ◽

Signaling Pathway ◽

Insulin Signaling ◽

Insulin Signaling Pathway ◽

Glucose And Lipid Metabolism ◽

Kkay Mice ◽

Hepatic Glucose

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The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance

Endocrine Reviews ◽

10.1210/er.2019-00034 ◽

2019 ◽

Vol 40 (5) ◽

pp. 1367-1393 ◽

Cited By ~ 33

Author(s):

Matthew J Watt ◽

Paula M Miotto ◽

William De Nardo ◽

Magdalene K Montgomery

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Liver Disorder ◽

The Body ◽

Limited Information ◽

Peripheral Tissues ◽

Nonalcoholic Fatty Liver ◽

Induce Insulin Resistance ◽

Glucose And Lipid Metabolism ◽

Physiological Processes

AbstractThe liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.

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