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10 pages, 1534 KiB

Open AccessArticle

Prevention of Lipotoxicity in Pancreatic Islets with Gammahydroxybutyrate

by Justin Hou Ming Yung, Lucy Shu Nga Yeung, Aleksandar Ivovic, Yao Fang Tan, Emelien Mariella Jentz, Battsetseg Batchuluun, Himaben Gohil, Michael B. Wheeler, Jamie W. Joseph, Adria Giacca and Mortimer Mamelak

Cells 2022, 11(3), 545; https://doi.org/10.3390/cells11030545 - 04 Feb 2022

Cited by 3 | Viewed by 2036

Abstract

Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an [...] Read more.

Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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19 pages, 3621 KiB

Open AccessArticle

CerS1 but Not CerS5 Gene Silencing, Improves Insulin Sensitivity and Glucose Uptake in Skeletal Muscle

by Agnieszka U. Błachnio-Zabielska, Kamila Roszczyc-Owsiejczuk, Monika Imierska, Karolina Pogodzińska, Paweł Rogalski, Jarosław Daniluk and Piotr Zabielski

Cells 2022, 11(2), 206; https://doi.org/10.3390/cells11020206 - 08 Jan 2022

Cited by 8 | Viewed by 1976

Abstract

Skeletal muscle is perceived as a major tissue in glucose and lipid metabolism. High fat diet (HFD) lead to the accumulation of intramuscular lipids, including: long chain acyl-CoA, diacylglycerols, and ceramides. Ceramides are considered to be one of the most important lipid groups [...] Read more.

Skeletal muscle is perceived as a major tissue in glucose and lipid metabolism. High fat diet (HFD) lead to the accumulation of intramuscular lipids, including: long chain acyl-CoA, diacylglycerols, and ceramides. Ceramides are considered to be one of the most important lipid groups in the generation of skeletal muscle insulin resistance. So far, it has not been clearly established whether all ceramides adversely affect the functioning of the insulin pathway, or whether there are certain ceramide species that play a pivotal role in the induction of insulin resistance. Therefore, we designed a study in which the expression of CerS1 and CerS5 genes responsible for the synthesis of C18:0-Cer and C16:0-Cer, respectively, was locally silenced in the gastrocnemius muscle of HFD-fed mice through in vivo electroporation-mediated shRNA plasmids. Our study indicates that HFD feeding induced both, the systemic and skeletal muscle insulin resistance, which was accompanied by an increase in the intramuscular lipid levels, decreased activation of the insulin pathway and, consequently, a decrease in the skeletal muscle glucose uptake. CerS1 silencing leads to a reduction in C18:0-Cer content, with a subsequent increase in the activity of the insulin pathway, and an improvement in skeletal muscle glucose uptake. Such effects were not visible in case of CerS5 silencing, which indicates that the accumulation of C18:0-Cer plays a decisive role in the induction of skeletal muscle insulin resistance. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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21 pages, 4891 KiB

Open AccessArticle

Carnosic Acid Attenuates the Free Fatty Acid-Induced Insulin Resistance in Muscle Cells and Adipocytes

by Danja J. Den Hartogh, Filip Vlavcheski, Adria Giacca, Rebecca E. K. MacPherson and Evangelia Tsiani

Cells 2022, 11(1), 167; https://doi.org/10.3390/cells11010167 - 05 Jan 2022

Cited by 14 | Viewed by 2861

Abstract

Elevated blood free fatty acids (FFAs), as seen in obesity, impair insulin action leading to insulin resistance and Type 2 diabetes mellitus. Several serine/threonine kinases including JNK, mTOR, and p70 S6K cause serine phosphorylation of the insulin receptor substrate (IRS) and have been [...] Read more.

Elevated blood free fatty acids (FFAs), as seen in obesity, impair insulin action leading to insulin resistance and Type 2 diabetes mellitus. Several serine/threonine kinases including JNK, mTOR, and p70 S6K cause serine phosphorylation of the insulin receptor substrate (IRS) and have been implicated in insulin resistance. Activation of AMP-activated protein kinase (AMPK) increases glucose uptake, and in recent years, AMPK has been viewed as an important target to counteract insulin resistance. We reported previously that carnosic acid (CA) found in rosemary extract (RE) and RE increased glucose uptake and activated AMPK in muscle cells. In the present study, we examined the effects of CA on palmitate-induced insulin-resistant L6 myotubes and 3T3L1 adipocytes. Exposure of cells to palmitate reduced the insulin-stimulated glucose uptake, GLUT4 transporter levels on the plasma membrane, and Akt activation. Importantly, CA attenuated the deleterious effect of palmitate and restored the insulin-stimulated glucose uptake, the activation of Akt, and GLUT4 levels. Additionally, CA markedly attenuated the palmitate-induced phosphorylation/activation of JNK, mTOR, and p70S6K and activated AMPK. Our data indicate that CA has the potential to counteract the palmitate-induced muscle and fat cell insulin resistance. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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Review

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10 pages, 3237 KiB

Open AccessFeature PaperReview

Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook

by Saeed Al Mahri, Shuja Shafi Malik, Maria Al Ibrahim, Esraa Haji, Ghida Dairi and Sameer Mohammad

Cells 2022, 11(4), 750; https://doi.org/10.3390/cells11040750 - 21 Feb 2022

Cited by 29 | Viewed by 4999

Abstract

Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent [...] Read more.

Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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23 pages, 3511 KiB

Open AccessReview

Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

by Eloisa Aparecida Vilas-Boas, Davidson Correa Almeida, Leticia Prates Roma, Fernanda Ortis and Angelo Rafael Carpinelli

Cells 2021, 10(12), 3328; https://doi.org/10.3390/cells10123328 - 26 Nov 2021

Cited by 24 | Viewed by 4325

Abstract

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown [...] Read more.

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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18 pages, 1499 KiB

Open AccessReview

The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity

by Qutuba G. Karwi, Qiuyu Sun and Gary D. Lopaschuk

Cells 2021, 10(11), 3259; https://doi.org/10.3390/cells10113259 - 21 Nov 2021

Cited by 20 | Viewed by 4126

Abstract

Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic [...] Read more.

Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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29 pages, 2252 KiB

Open AccessFeature PaperReview

Mechanisms Driving Palmitate-Mediated Neuronal Dysregulation in the Hypothalamus

by Calvin V. Lieu, Neruja Loganathan and Denise D. Belsham

Cells 2021, 10(11), 3120; https://doi.org/10.3390/cells10113120 - 11 Nov 2021

Cited by 5 | Viewed by 3581

Abstract

The hypothalamus maintains whole-body homeostasis by integrating information from circulating hormones, nutrients and signaling molecules. Distinct neuronal subpopulations that express and secrete unique neuropeptides execute the individual functions of the hypothalamus, including, but not limited to, the regulation of energy homeostasis, reproduction and [...] Read more.

The hypothalamus maintains whole-body homeostasis by integrating information from circulating hormones, nutrients and signaling molecules. Distinct neuronal subpopulations that express and secrete unique neuropeptides execute the individual functions of the hypothalamus, including, but not limited to, the regulation of energy homeostasis, reproduction and circadian rhythms. Alterations at the hypothalamic level can lead to a myriad of diseases, such as type 2 diabetes mellitus, obesity, and infertility. The excessive consumption of saturated fatty acids can induce neuroinflammation, endoplasmic reticulum stress, and resistance to peripheral signals, ultimately leading to hyperphagia, obesity, impaired reproductive function and disturbed circadian rhythms. This review focuses on the how the changes in the underlying molecular mechanisms caused by palmitate exposure, the most commonly consumed saturated fatty acid, and the potential involvement of microRNAs, a class of non-coding RNA molecules that regulate gene expression post-transcriptionally, can result in detrimental alterations in protein expression and content. Studying the involvement of microRNAs in hypothalamic function holds immense potential, as these molecular markers are quickly proving to be valuable tools in the diagnosis and treatment of metabolic disease. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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13 pages, 1070 KiB

Open AccessFeature PaperReview

Effects of Obesogenic Feeding and Free Fatty Acids on Circadian Secretion of Metabolic Hormones: Implications for the Development of Type 2 Diabetes

by Alexandre Martchenko and Patricia Lee Brubaker

Cells 2021, 10(9), 2297; https://doi.org/10.3390/cells10092297 - 03 Sep 2021

Cited by 9 | Viewed by 2395

Abstract

Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental [...] Read more.

Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental factors such as shift work, significantly increases the risk for the development of metabolic diseases, including type 2 diabetes and obesity. More recently, obesogenic feeding and its fatty acid components have also been shown to be potent disruptors of normal circadian biology. Two key hormones that are released in response to nutrient intake are the anti-diabetic incretin hormone glucagon-like peptide-1, from intestinal L cells, and insulin secreted by pancreatic β cells, both of which are required for the maintenance of metabolic homeostasis. This review will focus on the circadian function of the L and β cells and how both obesogenic feeding and the saturated fatty acid, palmitate, affect their circadian clock and function. Following introduction of the core biological clock and the hierarchical organization of the mammalian circadian system, the circadian regulation of normal L and β cell function and the importance of GLP-1 and insulin in establishing metabolic control are discussed. The central focus of the review then considers the circadian-disrupting effects of obesogenic feeding and palmitate exposure in L and β cells, while providing insight into the potential causative role in the development of metabolic disease. Full article

(This article belongs to the Special Issue Free Fatty Acids and Pathogenesis of Diabetes Mellitus)

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