Mitochondrial Plasticity in Obesity and Diabetes Mellitus

Jeleník, Tomáš; Roden, Michael

doi:10.1089/ars.2012.4910

Cited by 62 publications

(41 citation statements)

References 76 publications

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“…BEZ treatment is also associated with a lower prevalence of type 2 diabetes in high-risk populations (5) and decreased blood glucose levels in patients with established type 2 diabetes (6). Since lipid and glucose metabolism are closely linked (7), the decreased prevalence of type 2 diabetes in BEZ-treated patients is not completely unexpected, although the underlying molecular mechanisms of BEZ action remain unclear.…”

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confidence: 99%

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

et al. 2016

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Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

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confidence: 99%

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

et al. 2016

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“…From a functional perspective, the study of the regulation of mitochondrial biogenesis has obvious implications for both human health and performance. Impaired mitochondrial function is associated with the pathology of many metabolic disorders such as insulin resistance and type 2 diabetes [2], obesity [3], ageing [4] and cancer [5]. In relation to exercise performance, the increased mitochondrial content that accompanies exercise training ensures that exercise in the trained state induces less disturbance to metabolic homeostasis for a given exercise intensity.…”

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confidence: 99%

The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-a protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53 Ser15 is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5 0 adenosine monophosphateactivated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guideli...

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“…As a result, mitochondria exhibit “plasticity” i.e. rapid alteration of their numbers and characteristics in response to metabolic fluctuations for meeting cellular needs [19,21,22]. Diet, exercise, insulin, and drugs strongly shape this plastic behavior and consequently mitochondrial health.…”

Section: Physiologymentioning

confidence: 99%

Obesity, Metabolic Syndrome, and Airway Disease

Agrawal

Prakash

2014

Immunology and Allergy Clinics of North America

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SYNOPSIS Common pathophysiological mechanisms are increasingly being recognized between obesity, metabolic dysfunction, and airway disease. Obesity increases asthma risk or severity, in multiple studies across the globe. Metabolic changes of obesity such as diabetes or insulin resistance are associated with asthma as well as poorer lung function. Insulin resistance has also been found to increase asthma risk independent of body mass. Conversely, asthma has been associated with abnormal glucose and lipid metabolism, insulin resistance, and obesity. These bidirectional and dose-dependent associations suggest common unifying molecular processes that contribute to these seemingly disparate diseases. Reduced mitochondrial mass and/or function is increasingly recognized as one such mechanism that has been causally associated with insulin resistance, obesity and asthma, while conversely, restoration of mitochondrial numbers and function can lead to recovery of normal bioenergetics with reversal of disease features. Here, we review current understanding of how dietary and lifestyle factors lead to changes in mitochondrial metabolism and cellular bioenergetics, inducing various components of the cardiometabolic syndrome as well as airway disease. We provide an overview of and evidence for potentially useful mitochondria-targeted therapies, and discuss the emerging use of mesenchymal stem cells as mitochondrial donors, in the context of asthma.

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Mitochondrial Plasticity in Obesity and Diabetes Mellitus

Cited by 62 publications

References 76 publications

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

The Emerging Role of p53 in Exercise Metabolism

Obesity, Metabolic Syndrome, and Airway Disease

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