Mitochondrial dysfunction in type 2 diabetes and obesity 6kg,can a diabetic person eat strawberries,effects of type 2 diabetes on endocrine system - Reviews

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The discovery of a "maternal age effect" by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells -- and the transmission of these mutations to children -- could provide valuable insights for genetic counseling.
The discovery of a maternal age effect by a team of Penn State scientists that could be used to predict the accumulation of mitochondrial DNA mutations in maternal egg cells -- and the transmission of these mutations to children -- could provide valuable insights for genetic counseling.
The multidisciplinary research team set out to learn whether maternal age is important in the accumulation of mitochondrial DNA (mtDNA) mutations, both in the mother and in the child as a result of transmission. Through DNA sequencing, they found more mutations in blood and cheek cells in the older mothers in the study.
Although weight loss and tight glucose control may be more difficult in older people with diabetes, these interventions work in middle-aged people with type 2 diabetes. Finally, although glycemic control is the primary goal of diabetes treatment, and current diabetes medications help control blood glucose levels, we should carefully consider the value of diabetes medications with neuroprotective actions. Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. Garcia-Roves2, 3[1] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[2] Diabetes and Obesity Laboratory, August Pi i Sunyer Biomedical Research Center (IDIBAPS),, Spain[3] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona,, Spain1. In a normal mitochondrion (left) these folds fill the interior, but these folds are lost in damaged or dysfunctional mitochondria (right). These mutations cause more than 200 diseases and contribute to others such as diabetes, cancer, Parkinson's disease, and Alzheimer's disease.
In elderly people with Alzheimer’s disease, cognitive dysfunction attributable to this condition can make it hard to monitor blood glucose levels and take their insulin.
In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. IntroductionPhosphorylation, acetylation, ubiquitinylation, and glycosylation are among the most well-known post-translational modifications. Introduction“Let food be your medicine and medicine be your food” stated Hippocrates, the father of Western medicine, in 400 B.C. The study found greater rates of the mitochondrial DNA variants in children born to older mothers, as well as in the mothers themselves.
Hershey Medical Center, they took samples of blood and of cells inside the cheek from 39 healthy mother-child pairs.
The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues. The concept of protein oxidation as a post-translational modification has only recently gained acceptance.
Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacity7.2.
This statement was based on the belief that food was able to influence disease, a concept that was revived several times in later years by painters, writers, scientists, and philosophers.
The research will be published in the early online edition of the Proceedings of the National Academy of Sciences on October 13, 2014.Mitochondria are structures within cells that produce energy and that contain their own DNA. The researchers believe a similar mutation process is occurring both in the cells of the mothers' bodies and in their germ lines.The study led to another important discovery about egg-cell development.
Protein oxidation occurs as an outcome of a chemical attack by reactive oxygen species (ROS) or reactive nitrogen species (RNS) on susceptible amino acids, such as tyrosine, tryptophan, histidine, lysine, methionine, and cysteine [1].
One such philosopher, Ludwig Feuerbach, famously wrote in his 1863-4 essay “man is what he eats” introducing the idea that if we want to improve the spiritual conditions of people we must first improve their material conditions (Feuerbach, 2003). Studying healthy individuals gave the researchers a baseline for future studies of disease-causing mutations.
Although it was known that developing egg cells go through a "bottleneck" period that decreases the number of mtDNA molecules, scientists didn't know how small or large this bottleneck is. These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification. Indeed, it is important to note that signal transduction must occur in a coordinated manner in response to a stimulus. However, for years his warnings remained unheeded, at least in Western countries, in contrast to the teachings of Indian and Chinese medicine which for millennia have argued that a living organism has to assume a healthy diet.
A large number of scientific studies have highlighted the importance of ROS as a second messenger in numerous cellular processes, including cell proliferation, gene expression, adhesion, differentiation, senescence, and apoptosis. Like diet, physical activity has been also considered an important starting point for people's health.
In this context, the goal of this review is to discuss the mechanisms by which PKCs are modulated by ROS and how these processes are involved in the cellular response. In this way, an oxidation-dependent chain reaction may be short and employ only a low concentration of oxidants to avoid irreversible damage to cellular components. Hippocrates wrote in his book Regimen "if we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health" (Hippocrates, 1955). What we discovered is that this bottleneck is indeed very small."This finding is especially important for mothers who have a mitochondrial disease. Thus, proteins that are reversibly modulated by these reactant molecules are of high interest. Our knowledge about the links between diet, exercise, and disease has vastly increased since Hippocrates time. For many mitochondrial diseases, 70 to 80 percent of molecules need to have the disease-causing variant for the disease to manifest itself. Kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events [3–6]. A healthy lifestyle based on diet and physical activity is now considered the keystone of disease prevention and the basis for a healthy aging. But for others, only 10 percent of the mtDNA molecules with the variant are needed to cause disease.
The major mechanism by which these proteins are modified by oxidation involves the presence of key redox-sensitive cysteine residues [7].The goal of this review is to discuss the mechanisms by which protein kinase Cs (PKCs) can be modulated by ROS and how these processes are involved in the cellular response.
However, modern society has created conditions with virtually unrestricted access to food resources and reduced physical activity, resulting in a positive overall energy balance.
The review will focus on the structural mechanism of action of ROS in the activity of these enzymes, how ROS interact with their target molecules, the regulation of these enzymes by oxidants, and finally the major consequences of this tightly controlled mechanism on cell signaling. This is far from the environment of our ”hunter-gathered ancestros” whose genes were modulated over thousands of years adapting our metabolism to survive when food was scarce and maximizing energy storage when food became available.
In terms of evolution, this radical and sudden lifestyle change in modern society has led to a dramatic increase in the incidence of metabolic diseases including obesity and type 2 diabetes mellitus (T2DM).
It seems clear that the development of T2DM has a genetic component that becomes obvious when individuals are exposed to western lifestyle.
However, environment plays a critical role in the incidence of the disease being obesity the main etiological cause of T2DM. We have now added another set of genetic disorders that also might be affected by the age of the mother. Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistance6.1. Thus, modest weight loss is enough for obese glucose intolerant subjects to prevent the development of T2DM (National Task Force on the Prevention and Treatment of Obesity, 2000).T2DM also known as “non-insulin-dependent diabetes mellitus” or “adult-onset diabetes”, is a metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency.
T2DM is now considered to be a global epidemic with significant social and economic consequences both at the individual and population level.
The International Diabetes Federation estimates that 366 million people suffered from this disease in 2011 and predicts that these numbers will increase to 552 million people by 2030.
The team also includes Ben Dickins at Nottingham Trent University in the United Kingdom and Thorfinn Korneiussen and Rasmus Nielsen at the University of California-Berkeley.The research was funded by Penn State's Huck Institutes of Life Sciences, the Pennsylvania Department of Health, Battelle Memorial Institute, and Penn State's Clinical and Translational Sciences Institute. The pathophysiology of prediabetes is characterized by alterations in insulin sensitivity and pancreatic beta-cell function, usually associated with increased adiposity (Dagogo-Jack et al., 2009). While these data are encouraging, these interventions are costly, require a very high degree of commitment of the subjects, and are not always successful.
Although the progress in understanding the metabolic derangements of T2DM has led to significant advances in the treatment of this disease, it remains unclear whether current therapeutic approaches can really improve the underlying metabolic defects. Therefore, there is an urgent need to characterize the complex pathophysiology of the disease, to identify and target specific mechanisms in order to slow down the worldwide diabetes epidemic.2. There are three distinct phosphorylation sites in the catalytic domain; the first and rate-limiting phosphorylation step occurs in the activation loop sequence [10,15].
Insulin action and insulin resistanceInsulin essentially provides an integrated set of signals that allow for the balancing of nutrient availability and caloric demands (Samuel et al., 2010).
Phosphoinositide-dependent kinase-1 (PDK-1) is the upstream kinase that directly phosphorylates the activation loop of many PKCs [10,15,18]. In collaboration with the opposing hormone glucagon, it is responsible for maintaining glucose homeostasis, which is necessary to ensure proper function and survival of all organs. The regulation of plasma glucose concentrations is vital for the entire body and both hypoglycemia and hyperglycemia can impair whole-body physiology, ultimately leading to cellular death. PDK-1 directs the activation of aPKCs, such as ?, in a phosphoinositide 3-kinase (PI3K)-dependent manner. This is why it is critical to regulate and maintain plasma glucose levels around 5mM, the physiological set point in mammals (Saltiel, 2001).The primary targets of insulin action to maintain glucose homeostasis are skeletal muscle, liver, and adipose tissue. Under physiological conditions, carbohydrates provided by the diet increase plasma glucose levels and promote insulin secretion from pancreatic ? cells of the islets of Langerhans. The PI3K pathway produces inositol phospholipids containing an additional phosphate at the third position, which activate PDK-1 and aPKC [19].
Once secreted, insulin binds to its receptor, triggering a cascade of downstream phosphorylation events that expand the initial signal (Figure 1). However, the phosphorylation at the activation loop of the cPKC and nPKC isozymes does not activate but rather promotes the autophosphorylation of two residues at the C-terminus. Insulin binds to its receptor and activates its intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face. The first residue has been termed the “turn motif” because it is flanked by a proline residue, and the terminal site is called the “hydrophobic motif” because it is flanked by hydrophobic amino acid residues. The activated receptor, in turn, recruits and phosphorylates a group of substrate molecules. The autophosphorylation produces a mature and fully phosphorylated enzyme that is able to respond to lipid second messengers [10,15,18,20].Phospholipase C (PLC) is an enzyme that, when activated by growth factor receptors, hydrolyzes phosphatidylinositol 4, 5-bisphosphate (PIP2) to generate DAG and inositol trisphosphate (IP3), which subsequently mobilize intracellular calcium [21]. They have the role of docking proteins and are known as “insulin receptor substrates” (IRS). In the absence of activating cofactors, such as Ca2+ and DAG, PKCs are maintained in an inactive conformation by binding of the PS to the substrate-binding cavity [11,20].
Among these, IRS1 and IRS2 appear to be the major adapter molecules that play a role in insulin cascade.
The cPKCs are activated by both DAG, which binds to the C1 domain, and Ca2+, which binds to the C2 domain. After Ca2+ signaling, the binding of DAG to the C1 domain increases the affinity of PKCs for membrane lipids, inducing conformational changes that lead to a catalytically competent form. Recent studies indicate the existence of another model in which cellular stimulation results in inducible phosphorylation at some of the three sites in PKCs [24–26].
This event relieves the inhibitory phosphorylation of glycogen synthase (GS), which becomes activated and promotes glycogen synthesis;insulin-stimulated translocation of the glucose transporter GLUT4 at the plasma membrane, resulting in increased glucose uptake. Generally, activation is characterized by the translocation of the PKC from the cytosol to the plasma membrane [27]. However, the isoforms have different subcellular localizations, and this simple model cannot be applied for all of them.
AS160 normally inhibits translocation of GLUT4 through its interaction with RabGTPase protein. The inhibitory phosphorylation of AS160 favors the GTP-loaded state of Rab and relieves the inhibitory effect on GLUT4, stimulating its translocation to the plasma membrane.
Pathogenesis of Type 2 Diabetes MellitusAn important early phenotype associated with increased T2DM risk is insulin resistance. Given these data, it is alarming that the high prevalence of insulin resistance in the population predicts further dramatic increases in the worldwide epidemic of T2DM. Individuals with established T2DM show several physiological abnormalities, including elevation in fasting glucose levels, elevation in postprandial glucose levels, or both. In adipose tissue, the major fat storage tissue in mammals, insulin resistance results in increased lipolysis and fatty acid release. Increased circulating fatty acids decrease the ability of insulin to suppress hepatic glucose production and allow a constant increase in fatty acid synthesis. Regulation of Protein Kinase C by Reactive Oxygen Species (ROS)Reactive oxygen species (ROS) are produced in the natural course of metabolism. This dysregulation of carbohydrate and lipid metabolism accelerates the progression of insulin resistance. They can originate from different sources, including the mitochondrial electron transport chain, xanthine oxidase, myeloperoxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox enzymes), and lipoxygenase [3,25]. During the first stages of the development of the disease, pancreatic beta-cells have the ability to compensate for insulin resistance by increasing basal and postprandial insulin secretion to correct hyperglycemia. Nox enzymes and lipoxygenase are responsible for the production of ROS in response to hormones, growth factors and cytokines [34–36].
When pancreatic beta-cells can no longer compensate they become unable to respond appropriately to glucose levels.
Among these oxygen metabolites are superoxide anions (O2 ?), hydrogen peroxide (H2O2) and hydroxyl radicals (·OH) [26]. This pancreatic beta-cell failure leads to the deterioration of glucose homeostasis and the development of T2DM.
This pattern of physiological abnormalities in skeletal muscle, adipose tissue, liver, and pancreas presents itself in the late stages of the disease (Saltiel, 2001).
Many of them have very short half-lives, leading to little relevance in terms of signaling. Additionally, abnormal secretion and regulation of incretins in the gastrointestinal tract, hyperglucagonemia due to alterations in pancreatic alpha-cells, increased glucose reabsorption in kidney, and altered balance of central nervous system pathways involved in food intake and energy expenditure play an important role in the development of T2DM (Defronzo, 2009). For example, the •OH is the most unstable radical, reflecting its limited ability to transmit signals across any significant distance.
This complex pathophysiology makes difficult to identify the primary events responsible for the development of T2DM.4. In addition, O2 ? and H2O2 can be considered more stable species, and because of this feature, they may be the most favorable ROS to operate as signaling molecules [37]. Skeletal muscle insulin resistance and T2DMAs mentioned above, insulin resistance is a key component for the development of T2DM. ROS were once considered a dangerous product of cellular metabolism because, in high concentrations, they deleteriously affect DNA, lipids and proteins. Currently, these reactant molecules, in lower doses, are thought to act as important mediators of cell growth, adhesion, differentiation, senescence, and apoptosis by modifying key elements in protein regulatory sites [3,25].In the PKC structure, two pairs of zinc fingers are found within the regulatory domain.
Himsworth and Kerr, using a combined oral glucose and intravenous tolerance test, were the first to demonstrate that tissue-specific insulin sensitivity was lower in T2DM individuals (Himsworth, 1940). Ginsberg and colleagues provided another important evidence related to the decreased ability of insulin to promote glucose uptake in subjects with T2DM (Ginsberg et al., 1975).

Each zinc finger is formed by a structure that is composed of six cysteine residues and two zinc atoms, as presented in Figure 2. Later on, clear evidences about skeletal muscle insulin resistance in T2DM subjects were provided by DeFronzo and colleagues, who used the euglycemic-hyperinsulinemic clamp technique to quantify insulin-stimulated glucose uptake. The high levels of cysteine residues render the regulatory domain susceptible to redox regulation [11,23].
The oxidants destroy the zinc finger conformation [38], and the autoinhibition is relieved, resulting in a PKC form that is catalytically active in the absence of Ca2+ or phospholipids. Skeletal muscle is the largest insulin-sensitive organ in humans accounting for more than 80% of insulin stimulated glucose disposal (DeFronzo et al., 1985). Cysteine residues are also found in the C-terminal catalytic domain, but they are uncoordinated in a different manner to those in the regulatory domain. Redox modifications at the C-terminal catalytic domain lead to the inactivation of the kinase due to the loss of the free sulfhydryls required for its catalytic activity. Moreover, several evidences linked mitochondrial defects to insulin resistance and T2DM (Lowell and Shulman, 2005), suggesting that these organelles are key players in maintaining energy homeostasis.In this chapter we will discuss the potential role that mitochondrial dysfunction plays in T2DM etiology. Furthermore, the intracellular redox state has been shown to affect the distribution of the PKC isoforms [11,23].
Because all PKC isoforms possess zinc fingers and high concentration of cysteine residues located in the regulatory domain, as well as free sulfhydryls in the catalytic site, it seems that the regulation by oxidation is a common feature for this family.
However, this signaling mechanism may vary according to the distinct isoform and different cell [11]. Skeletal muscle fiber types and metabolismSkeletal muscle is a complex tissue composed of different fiber types, which have distinct mechanical and metabolic properties. The aPKCs, for example, lack one of the two cysteine-rich zinc-finger regions in the regulatory domain [39].
Each of these functional systems is composed of a motor neuron and a group of muscle fibers.
In mouse embryonic fibroblasts, oxidative stress triggers translocation of PKC?, ?, ?, and ? isoforms from the cytosol to the plasma membrane. In adult human skeletal muscle type 2B fibers are not detectable and the oxidative capacity of type 2X fibers is lower than that observed in rats and mice (Schiaffino and Reggiani, 2011).
PKC? selectively regulates the activation of the inducible nuclear factor ?B (NF-?B) in response to oxidative stress. For additional reading we recommend a review published in Physiological Reviews written by Stefano Schiaffino and Carlo Reggiani that provides an up to date and detailed understanding of this topic (Schiaffino and Reggiani, 2011). The activation of the transcription factor NF-?B is often observed in cells exposed to oxidative stress [40]. For the purposes of this discussion, it is important to keep in mind skeletal muscle diversity: distinct skeletal muscle fibers differ in their energy requirements for cellular function, including contractile activity.
Energy is provided by adenosine triphosphate (ATP) hydrolysis to adenosine diphosphate (ADP) and inorganic phosphate (Pi). This coordinated mechanism seems to be specifically in response to oxidative stress, and relies on the activation of PKC? and not of other PKC isoforms [41].
ATP can be generated by three main mechanisms that vary in their capacity and velocity to resynthesize ATP.
The Phosphocreatine (PCr)-creatine kinase (CK) system corresponds to a high-power and low-capacity ATP production reservoir. Glycolysis is the metabolic process by which glycogen and glucose are metabolized to pyruvate and subsequently to lactate; this process has a lower power but a higher capacity for ATP generation than the PCr-CK system. The specificity by which ROS may activate different PKC isoforms is not well established, but the localization and the intensity of ROS generation could contribute to the explanation of such different responses. The other energy production resource is the mitochondrial oxidative phosphorylation system, which can obtain ATP from different substrates: pyruvate, fatty acids, amino acids, and ketone bodies. The oxidative phosphorylation system has a very high capacity for ATP generation but a lower power when compared to the other two ATP production systems.
It is also important to highlight that mitochondrial mediated ATP resynthesis is highly dependent on oxygen and substrate availability.Due to its intrinsic characteristics, slow and fast muscle fibers differ in their relative contribution to energy production from PCr-CK, glycolysis, and oxidative phosphorylation processes. The relative contribution of these metabolic pathways is mostly established during differentiation according to the specific function and energy demands of each fiber type.
Thus, skeletal muscle is able to predominantly utilize both glucose and free fatty acids as fuel sources for energy production.
This event, together with the activation of key enzymes in glucose metabolism, leads to a marked increase in muscle glucose oxidation. After glucose is transported into the myocytes trough the GLUT4 transporter, it is immediately phosphorylated by hexokinase II, and the phosphorylated glucose is stored as glycogen or enters the glycolytic pathway for energy production. Thus, during feeding conditions, the main source for energy production in skeletal muscle is glucose.Therefore, muscle energy metabolism has to be capable of switching from predominant oxidation of fatty acids during fasting state, to predominant oxidation of glucose during feeding state. However, obese and type 2 diabetic subjects are unable to shift between substrates (fatty acids or glucose) demonstrating a high degree of metabolic inflexibility (Kelley et al., 1999). This inability to oxidize one substrate or another results in impaired glucose and fatty acid storage as glycogen and triglycerides, respectively. Pathogenesis of Insulin Resistance in Skeletal MuscleBoth obese subjects with or without T2DM have marked skeletal muscle insulin resistance compared to lean non-diabetic subjects.
The severity of the insulin resistance positively correlates with BMI (DeFronzo, 1982, Wedick et al., 2009). The mechanism through which obesity causes insulin resistance in skeletal muscle seems to be associated with the accumulation of fatty acids in the myocytes.
Among the various types of fatty acids, saturated long-chain ones, including palmitic and stearic acids, are strong inducers of insulin resistant state (Hirabara et al., 2009).
Obese subjects with or without T2DM are characterized by an increase in plasma fatty acid concentration, which strongly correlates with reduced insulin-stimulated glucose disposal in skeletal muscle.In normal conditions, fatty acids are stored in the adipose tissue as triglycerides and released during fasting.
During the postprandial state, blood glucose stimulates insulin secretion, which inhibits lipolysis in adipose tissue, therefore limiting the release of fatty acids. In insulin resistant individuals, the ability of insulin to inhibit lipolysis and reduce plasma fatty acid concentration is markedly impaired (Groop et al., 1991). They observed that incubation of rat heart with fatty acids was associated with an increase in intracellular concentrations of glucose-6-phosphate (G6P) and glucose. Moreover, incubation of diaphragm muscle with fatty acids led to an increase in glycogen accumulation. Accumulation of citrate inhibits phosphofructokinase and increases intracellular concentrations of G6P, leading to activation of glycogen synthesis, inhibition of hexokinase II, increase in intracellular glucose content and, consequently, reduction in glucose uptake.
Thus, this model is based on the inverse relationship between fatty acid availability and glucose utilization. If there was a block at the hexokinase step, as proposed by Randle, intra-myocellular glucose concentrations would be expected to increase. Instead, they noted that plasma fatty acid concentrations decreased the accumulation of intra-myocellular glucose, indicating that insulin-stimulated glucose transport activity was reduced.
ER is an intracellular membranous network responsible for synthesis, folding, maturation, trafficking and targeting of secreted and transmembrane proteins. In some diseases, protein synthesis increases in ER-lumen and proteins cannot fold correctly, affecting ER homeostasis. Impairment of ER homeostasis activates an elaborate adaptive stress response, known as “unfolded protein response” (UPR), and results in the phosphorylation and activation of JNK.
The link between T2DM, insulin resistance and ER stress in skeletal muscle is still unclear. It has been demonstrated that ER stress occurs in vivo in skeletal muscle when mice are fed a high fat diet (Deldicque et al., 2010a). Fatty acids activate inflammatory signals by promoting secretion of pro-inflammatory cytokines including TNFalpha, IL-1beta, and IL-6. Furthermore, fatty acids can directly interact with members of the Toll-like receptor (TLR) family, promoting activation of JNK and IKKbeta.
This activation leads to degradation of the inhibitor of kappa beta (IKB) and Nuclear factor-kappa beta (NFKB) activation.
PKC Phosphorylates Nox Subunits for ROS GenerationNox enzyme is a complex multi-subunit enzyme that uses NADPH as a substrate to convert molecular oxygen into ROS (mainly O2 ? with secondary production of H2O2) in a regulated manner in response to different stimuli, including growth factors, cytokines and calcium signals [68,69]. The prototypical Nox enzyme from phagocytic cells is divided into two parts: a membrane bound component, the flavocytochrome b558, which is composed of two subunits, a large glycosylated gp91phox that forms the catalytic subunit and the smaller regulatory subunit p22phox, and a cytosolic component formed by four major proteins, the regulatory subunits p47phox, p67phox, and p40phox, and the small GTPase RAC [70–73]. To date, seven mammalian isoforms are known (Nox1-5, Duox1, 2) to be expressed in a wide variety of tissues, such as vascular smooth muscle, kidney, spleen, cerebrum, lungs, colon, ovary and others [74]. Biology of the mitochondriaMitochondria are doubled-membrane organelles that constitute the major site for oxidative energy production in the cell.
When cells are stimulated, the cytosolic components migrate almost instantly to the membrane, where they assemble with the flavocytochrome b558 to form the active enzyme, a process that is tightly regulated by protein-protein interactions and phosphorylation of the p47phox subunit [68,70–73,75].PKC isoforms are upstream regulators of Nox. Mitochondria are the only mammalian organelles that contain extra-nuclear DNA (mtDNA), which encodes for 37 genes including 13 subunits of the electron transport chain (Kelly and Scarpulla, 2004). The activity of these enzymes is important for the assembly and activation of the Nox1-3 isoforms, which require the phosphorylation-dependent assembly of several cytosolic subunits to be catalytically active; this includes p47phox, which is the best studied of the phosphorylated Nox enzyme components [76]. Besides generating the majority of cellular ATP via oxidative phosphorylation (OXPHOS), many other essential cellular functions take place in this organelle.
The C-terminal sequence of p47phox has a basic charge, is rich in serine and arginine residues and has at least one proline-rich region (PRR) (amino acids 363–368) [71,77].
In resting cells, p47phox is not phosphorylated and possesses a highly basic charge (pI > 9). Oxidative phosphorylation (OXPHOS)Mitochondria are able to generate energy by oxido-reduction reactions and proton translocation derived from carbohydrates (TCA cycle), amino acids and fatty acids (?-oxidation). Upon phosphorylation, its pI shifts to the acidic range, giving rise to several phosphorylated isoforms, which correspond to different phosphorylated states [71,78]. For this purpose, oxygen is consumed to generate water, heat and adenosine triphosphate (ATP). Different PKC isoforms in various tissues have been described to be efficient in the phosphorylation of the p47phox subunit, as summarized in Table 1. The inner membrane invaginations of the mitochondria, called cristae, contain all transmembrane proteins of the electron transfer system (ETS) and the ATP synthase (Benard and Rossignol, 2008, Vonck and Schafer, 2009).
On the other hand, both Nox4 and Nox5 do not require cytosolic subunits for their activation. All components of the TCA cycle and ?-oxidation pathway are located inside the mitochondrial matrix. Nox4 is a constitutively active enzyme and is bound to the integral membrane protein p22phox, whereas Nox5 is primarily regulated by calcium levels [79,80].PKC is not the only protein kinase able to phosphorylate p47phox. Oxidation of substrates generates reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) that will provide electrons to the ETS.
Electrons flow from donors (NADH at complex I and FADH2 at complex II) to an oxygen molecule forming H2O at complex IV.
In vascular smooth muscle cells (VSMC), for example, three isoforms of Nox enzymes are present, Nox1, Nox2, and Nox4. There is a parallel translocation of protons to the intermembrane space from the matrix that creates an electrochemical gradient used by ATP synthase in a coupled manner to generate ATP.
This electrochemical gradient can also dissipate through uncoupling proteins (UCPs) using a non-ATPase-coupled proton leak and generating heat in a process called thermogenesis.
It seems that Nox1, when activated, is present on the cell surface and co-localizes with caveolins, while Nox2 can be located intracellularly or in the cell membrane. The high electronegative potential generated can also drive the entry of calcium into the matrix.
In this model, Nox4 plays an important role in the constitutive production of ROS, while Nox1 would be necessary during pathological development [122–124]. Mitochondrial biogenesis and dynamicsMitochondrial biogenesis is defined as the generation of more mitochondrial mass and takes place in response to increased energy demand. Recently studies showed that Nox1 expression is involved in the hypertrophy of VSMCs induced by aldosterone and prostaglandin F2?.
In both cases, the up-regulation of Nox1 may occur through the activation of PKC? and the activating transcription factor 1 (ATF1) [122,125,126].PKC can also activate Nox2. In human monocytes and murine macrophages PI3K and PKC pathways are involved in Nox2 stimulation in response to insulin. It has been recently established that mitochondrial fission and fusion contribute to multiple essential functions including calcium handling, ROS production and energy output (Chen and Chan, 2005, Parone et al., 2008, Soubannier and McBride, 2009). The relevance of these events in mitochondrial and cell physiology has been partially unraveled and observed that the disruption of such processes results in mitochondrial heterogeneity and dysfunction (Zorzano et al., 2009, Chan, 2006). Therefore, a fine-tune regulation of mitochondrial biogenesis and dynamics is necessary to obtain and maintain functional mitochondria.Mitochondrial biogenesis is a complex process that requires the expression of a large number of proteins encoded by both nuclear and mitochondrial genomes.
On the other hand, Nox4 seems to be related to smooth muscles cells or myofibroblasts and is independent of the pathological condition [128].Several studies demonstrate that Nox4 is inducible and can generate H2O2 in response to various hormone stimuli. The mitochondrial genome encodes only 13 proteins, which are essential subunits of the respiratory complexes.
Generation of H2O2 by Nox4 after insulin stimulation of differentiated adipocytes was shown to be important in both early and late events in insulin signal transduction, which includes the activation of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and the activation of downstream serine kinases and glucose uptake [129].
This genome also provides the 22 tRNAs and 2 rRNAs necessary for the translation of these mitochondrial-encoded proteins.
Similar results were found in preadipocytes, where Nox4 acts indirectly to facilitate the tyrosine phosphorylation of IRS-1, stimuli required for the insulin-induced differentiation of these cells [130]. In contrast, transcription of the mitochondrial genome is encoded by the nuclear genome, which is under the control of a single transcription factor named TFAM. Nox4 was also stimulated by H2O2 and diacylglycerol, through a mechanism dependent of phospholipase A2, but apparently independent of PKC activity. The arachidonic acid generated in this system by phospholipase A2 is responsible for the oxidase activation and the increase of intracellular ROS production [131], similar results were found in mesangial cells [132].It has been well established that angiotensin II exerts important intra–cellular signaling through ROS generation in many physiological and pathological conditions [133]. Therefore, fine-tuned coordination is required between the mitochondrial and the nuclear genomes to orchestrate the expression of proteins necessary for a successful mitochondrial biogenesis.
In many published works, angiotensin II has been shown to activate the Nox enzyme in a PKC-dependent manner [91,109,134–138].
This coordination is achieved by complex regulatory mechanisms that involve the action of a relatively small number of nuclear transcription factors, which are discussed in detail below. Apoptosis of cardiac cells mediated by alcohol is dependent on the angiotensin II interaction with the angiotensin II type 1 (AT1) receptor, which subsequently activates PKC?I to phosphorylate and activate the Nox enzyme.
These transcription factors are in turn regulated by cofactors that integrate physiological signals with the activity of the transcription factors to regulate mitochondrial biogenesis in response to environmental stimuli. Because high amounts of superoxide are generated in this process, this mechanism has also been related to alcoholic cardiomyopathy [134].
Angiotensin II also increased the basal and the NADPH stimulated superoxide production in coronary arteries, and this was found to be modulated by PKC activity [128].
Nuclear transcription factors involved in mitochondrial biogenesisThrough their DNA-binding domain, transcription factors bind to specific sequences in the gene promoter region to regulate transcription of a subset of genes. In addition, angiotensin II stimulates the epithelial Na+-channel in the rat cortical collecting duct through the activation of Nox-dependent PKC phosphorylation [135]. Several transcription factors have been shown to regulate expression of genes involved in the respiratory chain and mitochondrial metabolism, however only a few are considered the major transcription factors crucial for mitochondrial biogenesis. In the renal system, this receptor agonist has a stimulatory effect in a cross talk mechanism between the connecting tubule in the renal cortex and the afferent arteriole, which is mediated by O2? that is generated primarily by PKC-dependent Nox activation [132].

In physiological conditions, angiotensin II also regulates O2 ? generation in the thick ascending limb of the renal medulla through the activation of PKC? and the stimulation of NADPH oxidase [81]. Nuclear Respiratory Factor 1 (NRF-1)NRF-1 has a fundamental role in coordinating nuclear and mitochondrial transcription.
This mechanism is also associated with an increase in sodium absorption in this renal structure [136]. It induces expression of TFAM, TFB1M and TFB2M (Virbasius and Scarpulla, 1994, Gleyzer et al., 2005), which are essential proteins for the transcription of the mitochondrial genome, and also TOMM20, a key protein required for the transport of nuclear-encoded proteins into the mitochondria. Similar results were obtained for skeletal muscle [137] and monocytes, in which increased ROS generation by angiotensin II caused an increase in the level of interaction between human monocytes and the extracellular matrix by favoring adhesion to laminin-1 [108]. It has also been shown to regulate multiple subunits of the respiratory chain as well as other proteins involved in other mitochondrial functions.
Conversely, at the same time that angiotensin II triggers PKC-dependent Nox enzyme activation and ROS generation, it also stimulates the activity of antioxidant enzymes like catalase, SOD, and glutathione peroxidase (GPx) in the rat hypothalamus, a counteraction mechanism that exerts local control on ROS levels [138].Angiotensin II can also act as key neuromodulator in central autonomic nuclei [139,140].
Vagal afferent neurons, in the nucleus of the solitary tract, play a major role in cardiovascular regulation and are a target of angiotensin II through activation of the AT1 receptor.
This respiratory factor was named NRF-2 and was subsequently identified as the human homolog of the mouse GABP (Virbasius et al., 1993). In these cells intracellular Ca2+ and PKC activation are critical for AT1 receptor-induced Nox2 activation and ROS production. The authors suggest that this mechanism could play a role in the vascular dysregulation mediated by the central autonomic system [141].Phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) or PMA, are also involved in PKC-dependent Nox activation. Similarly to NRF-1, disruption of the NRF-2 gene also produces a lethal phenotype (Ristevski et al., 2004).
In human lung adenocarcinoma cells, the tumor-promoting TPA and the tumor necrosis factor-alpha (TNF-?) were implicated in the stimulation of the expression of the mitochondrial manganese-dependent isoform of SOD (MnSOD) mediated by the Nox enzyme pathway.
This stimulation is in part regulated by PKC?, which phosphorylates a transcription factor of cAMP-responsive element-binding protein, or by the PKC? pathway, which culminates with the activation of forkhead transcription factor 3 (FOXO3) [142].
Instead, it is a member of a family of orphan nuclear receptors that also include ERRbeta and ERRgamma.
In human umbilical vein endothelial cells, TNF-? was also shown to increase ROS generation via the PKC?II-dependent activation of vascular Nox enzyme.
Unlike NRF-1 and NRF-2 where gene knockout proves lethal, disruption of ERRalpha results in a viable phenotype showing decreased body weight and adipose depot size (Luo et al., 2003).
This mechanism has been suggested to be involved with apoptosis in these cells, but it occurs independently of ROS generation [144].
This mouse shows normal energy expenditure with no major decrease in mitochondrial proteins.
Other transcription factorsWhile not directly involved in transcription of mitochondrial biogenesis or respiratory chain genes, other transcription factors including PPARalpha, PPARdelta, and YY1 are also important for providing other mitochondrial proteins. PDBu increases superoxide generation by Nox2 through both p47phox and peroxide-dependent Src activation. The authors suggest that Nox2 contributes to vascular contractile mechanisms through PKC-dependent activation [148].Several works also highlight the participation of formyl peptide formyl-methionyl-leucyl-phenylalanine (fMLP) in the activation of PKC and Nox enzyme. This participation includes superoxide generation, which in turn stimulates leukocytes, phagocytic cells, and neutrophils [46,72,84,91,149,150].Although most biological functions of PKC have been recognized to occur at the plasma membrane or in the cytoplasm, several studies have pointed out the role of PKCs in nuclear functions [39]. PGC-1 coactivator familyWhile the transcription factors discussed above are part of the transcriptional machinery necessary for mitochondrial biogenesis, the members of the PGC-1 coactivator family provide the integration of physiological stimuli with the transcription factors to adapt mitochondrial biogenesis to changes in the environment. Almost all the isoforms of PKC have been identified at nuclear level, except for the PKC? isoform [39,151]. PGC-1 coactivators lack a DNA-binding domain, but they are able to interact with and activate several transcription factors by recruiting other cofactors with chromatin-remodeling activities (Monsalve et al., 2000). The distinct functions of PKCs in the nucleus may be a consequence of either, the activity of resident isoforms of the enzyme or the translocation of PKC from cytoplasm to the nucleus, which may occur in certain conditions and in a different cellular system, as a result of nuclear lipid signaling [39]. PPARgamma coactivator 1alpha (PGC-1alpha), the founding member of the PGC-1 family, was first identified by its ability to activate PPARgamma in brown adipocytes (Puigserver et al., 1998). PGC-1beta and PRC where subsequently identified based on their structural similarity with PGC-1alpha (Lin et al., 2002a, Andersson and Scarpulla, 2001). This PKC-? translocation through PtdIns(3,4,5)P3 signaling has been shown in nerve growth factor (NGF)-treated rat pheochromocytoma PC-12 cells [157,158], and in rat epatocytes treated with C2-ceramid [159].The nuclear presence of PKC suggests an involvement of these enzymes in the regulation of DNA replication, RNA synthesis and processing, gene expression, transport between nucleus and cytoplasm, and chromatin structure [39].
Moreover, nuclear PKCs have been implicated in cell proliferation, differentiation, apoptosis, and cardiovascular diseases [39,160]. For a complete review of nuclear PKCs and their function in cells see [39,151,161].Beside PKCs, Nox enzymes subunits have been described to be localized in subcellular compartments of different cells [162]. It is this regulatory capacity that allows PGC-1alpha to respond to physiological stimuli and activate the mechanisms leading to increased mitochondrial biogenesis.
This includes the presence of Nox1 and Nox4 in endoplasmic reticulum [79,163], Nox2 in perinuclear compartments [164], and Nox4 at the nucleus of multiple kinds of cells, such as endothelial cells, VSMCs, and hepatic cells [121,165,166]. Nox4 is considered the predominant NADPH isozyme in the kidney with prevalent expression in the proximal tubule [167,168]. Regarding these concepts, recent data show that angiotensin II can induce a nuclear Nox4-dependent generation of ROS, through PI3K and PKC activation in isolated nuclei of cortical cells of kidney [169].
Physical exercise has also been recognized as a main activator of mitochondrial biogenesis.
In the muscle cell, the AMP-dependent protein kinase (AMPK) responds to low energy levels (increase in AMP content) by inducing a signaling cascade that results in the activation of catabolic pathways and inhibition of anabolic pathways in an attempt to restore energy levels. Therefore, AMPK has been recognized as a key mediator in the physiological and metabolic adaptation to physical exercise.
Interestingly, AMPK can directly phosphorylate PGC-1alpha and activate its transcriptional activity regulating expression of mitochondrial genes (Jager et al., 2007). Mitochondrial dysfunction as a potential mechanism underlying skeletal muscle insulin resistanceMitochondrial adaptations (biogenesis and dynamics) and function largely affect muscle metabolism and have a significant impact on whole-body metabolism (Patti et al., 2010). As mentioned before, metabolic flexibility is defined as the ability to rapidly modulate substrate oxidation as a function of environmental, hormonal and different energy conditions (Storlien et al., 2004). Defects in pathways controlling glucose and energy homeostasis in skeletal muscle have been shown to impair these adaptations, leading to metabolic inflexibility. For the purposes of this chapter, we will define mitochondrial dysfunction as both the reduction in mitochondrial oxidative activity and in mitochondrial adenosine triphosphate (ATP) synthesis.
Early evidences relating insulin resistance and skeletal muscle mitochondrial dysfunctionSeveral key studies published between 1999 and 2005 laid the foundation for understanding the underlying mechanisms between mitochondrial dysfunction and subsequent insulin resistance in skeletal muscle and development of T2DM. Dysregulation of skeletal muscle fat oxidation in obesityThe first studies that identified a relationship between alterations in muscle metabolism and insulin resistance did not mention any link with mitochondrial dysfunction (Kelley et al., 1999). However, research performed by Kelley and co-workers addressed why the pattern of fatty acid utilization in skeletal muscle during fasting conditions might be associated with obesity-related insulin resistance, which is relevant for the scope of this chapter. The study included 16 lean and 40 obese volunteers with leg balance measurements of glucose and free fatty acid uptake. Indirect calorimetry across the leg was also measured in order to determine substrate oxidation during fasting and insulin-stimulated conditions. This study demonstrated that fatty acids were the predominant substrate oxidized by skeletal muscle during fasting conditions in lean subjects. However, rates of fatty acid oxidation during fasting were significantly lower in obese subjects, even though rates of fatty acid uptake were similar to those of lean subjects. Furthermore, the respiratory quotient values across the leg showed a reduced reliance on lipid oxidation in obese subjects. What it is also important is that weight loss only partially improved these patterns; the leg respiratory quotient in obese subjects was unchanged between pre- and post-weight loss, so the reliance of skeletal muscle in fat oxidation during fasting conditions was not improved.
The authors suggested that their data pointed to these defects as primary impairments leading to obesity, rather than resulting from obesity.
Muscle mitochondria in obesity and type 2 diabetesIn this study, Kelley and co-workers provided early evidence that mitochondrial dysfunction in human skeletal muscle contributes to the development of insulin resistance and progression to T2DM (Kelley et al., 2002b).
Previous work by the same group demonstrated that the severity of skeletal muscle insulin resistance in T2DM and obesity is related to diminished activity of oxidative enzymes (Simoneau and Kelley, 1997). Furthermore, triglyceride accumulation in skeletal muscle is also correlated with the severity of insulin resistance and with diminished oxidative enzyme activity. Because it was known that skeletal muscle depends on oxidative phosphorylation to produce energy and that insulin resistance in T2DM and obesity involves altered oxidation of carbohydrates and lipids, the authors attempted to elucidate the potential contribution of mitochondrial dysfunction to skeletal muscle insulin resistance in humans.
For this purpose vastus lateralis muscle samples from lean controls without T2DM, obese subjects with or without T2DM were obtained. An assessment of the activity of the mitochondrial OXPHOS system and a quantitative study of the mitochondria morphology by transmission electron microscopy was performed in the different muscle biopsies. Creatine kinase and citrate synthase activities were measured as markers of muscle fiber content and mitochondrial content, respectively. Results showed that skeletal muscle mitochondria structure and functional capacity were impaired in T2DM subjects and, to a lesser degree, in obese subjects. Mitochondrial respiratory complex I activity was reduced by 40% in skeletal muscle from subjects with T2DM when compared to lean controls without diabetes. Moreover, skeletal muscle mitochondrial area and size were smaller in obesity and T2DM and, in some instances, particularly in T2DM, severely damaged.
Although age can affect the size of mitochondria, in this case aging did not account for the ~30% reduction in size in obesity and T2DM.Based on their results, authors proposed a potential mechanism that could explain how impaired mitochondrial function leads to insulin resistance in skeletal muscle, which would be lipid accumulation within myocytes.
This was not a new finding, as previous studies (Kelley et al., 2002a) from the same group had shown that increased lipid accumulation in skeletal muscle is associated with insulin resistance and, in turn, lipid accumulation in skeletal muscle in obesity and T2DM is related to a reduced oxidative enzyme activity. Downregulation of oxidative metabolism genes in humans with insulin resistance and diabetesPatti and colleagues addressed how gene regulation was modulated by T2DM (Patti et al., 2003). The results showed that skeletal muscle from subjects with prediabetes and T2DM had decreased expression of oxidative phosphorylation genes, many of which are regulated by nuclear respiratory factor (NRF)-dependent transcription. A decreased expression of the co-activators PGC-1alpha and PGC-1beta, both of which induce NRF-dependent transcription, was also found. Therefore, subjects with insulin resistance and T2DM have a reduced expression of multiple (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesThis study extended the results obtained by Patti and colleagues (Patti et al., 2003). Mootha and co-workers used Gene Set Enrichment Analysis, designed to detect modest but coordinated changes in the expression of groups of functionally related genes to study differential expression among healthy individuals, impaired glucose tolerance subjects, and subjects with T2DM (Mootha et al., 2003). They named OXPHOS-CR to a subset of genes, which include about two-thirds of the OXPHOS genes, strongly expressed in skeletal muscle, heart and brown adipose tissue.
No relationship was found between body mass index (BMI) or waist-to-hip ratio and OXPHOS-CR expression, and neither between quantitative measures of fiber types and OXPHOS-CR. However, expression of OXPHOS-CR correlated positively with the aerobic capacity of the individuals under study and negatively to diabetes. In summary, a set of genes involved in oxidative phosphorylation, whose expression was coordinately decreased in skeletal muscle of T2DM subjects, were identified.
Thus, authors hypothesized that the decreased expression of OXPHOS-CR genes might contribute to T2DM. Impaired mitochondrial activity in insulin-resistant offspring of subjects with T2DMIn this study Petersen and co-workers aimed to determine the potential mechanism for the intra-myocellular accumulation of lipids leading to insulin resistance (Petersen et al., 2004). Young and lean insulin-resistant offspring of subjects with T2DM and insulin-sensitive subjects were studied. To test their hypotheses, authors utilized hyperinsulinemic-euglycemic clamps in these subjects to measured intra-myocellular lipid and intrahepatic triglyceride content, assessed whole-body and subcutaneous fat lipolysis rates and determined mitochondrial oxidative-phosphorylation activity in muscle by magnetic resonance spectroscopy. The insulin-stimulated rate of glucose uptake was 60% lower in the insulin-resistant subjects, which could be explained by a 70% reduction in insulin-stimulated non-oxidative muscle glucose metabolism.
They also observed an 80% increase in intra-myocellular lipid content and a 30% reduction in mitochondrial oxidative phosphorylation, suggesting that subjects with T2DM have an inherited reduction in mitochondrial content in muscle, which in turn may be responsible for the reduced rates of mitochondrial oxidative phosphorylation.
Putting the pieces together, the link between mitochondrial dysfunction and T2DMIn the year 2005 Drs. Lowell and Shulman wrote a viewpoint where they hypothesized that insulin resistance and hyperglycemia could be caused by a primary mitochondrial dysfunction (Lowell and Shulman, 2005). Insulin resistance occurs due to the accumulation of intracellular fatty acyl CoA and diacylglycerol, which in turn activate critical signal transduction pathways, leading to suppression of the insulin signaling pathway. DAG would then activate the phosphorylation of serines and threonines of the insulin receptor susbtrate 1 (IRS-1) through enzymes such as protein kinases C (PKC). PKCs activate the serine kinase cascade and increase the IRS-1 serine (Ser, S) phosphorylation of the the insulin receptor susbtrate 1 (IRS-1).
The phosphorylation of serines located in critical sites leads to a blockage of the IRS-1 tyrosines (Tyr, Y) phosphorylation by the insulin receptor, inhibiting insulin-induced phosphatidyl inositol 3-kinase activity (PI3-kinase) resulting in a decreased insulin-stimulated Akt activity.
Akt reduced activity fails to activate the translocation of GLUT4 to the membrane, diminishing the insulin-induced glucose uptake and impairing the removing of glucose from blood.It is still uncertain whether skeletal muscle mitochondrial dysfunction is a cause or rather a consequence of the metabolic derangements that contribute to insulin resistance in T2DM, including lipid accummulation, pro-inflammatory signals or endoplasmic reticulum stress.
However, given its complex pathophysiology, establishing causality has proved difficult and the mechanisms leading to insulin resistance remain elusive.7. These features, together with impaired energy substrate utilization and the observation that these deleterious effects are not restricted to skeletal muscle, led to the hypothesis that mitochondrial dysfunction plays a major role in T2DM etiology (Lowell and Shulman, 2005).
Since the publication of this hypothesis, there has been a growing interest in further assessing the potential implication of mitochondrial function in the etiology of this metabolic disease. One of the first attempts to clearly prove this hypothesis used transgenic mice with defective mitochondria in order to observe whether they would develop T2DM (Pospisilik et al., 2007). Earlier reports from this same group have shown that conditional deletion of apoptosis inducing factor (AIF) provokes OXPHOS dysfunction (Vahsen et al., 2004). Initially, AIF was considered as a mitochondrial protein involved in signaling events leading to cell death.
Subsequent studies have demonstrated that the primary physiological role of AIF is the maintenance of an efficient mitochondrial respiratory system. Studies assessing whole body glucose homeostasis and diet-induced obesity and diabetes either in tissue specific (liver and skeletal muscle) AIF knockout mice or in mice with ubiquitous OXPHOS defects showed that these mice were more insulin sensitive and were protected against diet-induced obesity and diabetes, in contrast with previous hypotheses (Pospisilik et al., 2007). Recently, this observation has been confirmed in another study using rats fed with an iron-deficient diet, which provokes a reduction in the iron containing proteins of OXPHOS (Han et al., 2011). Controversy about the effects of high fat diet feeding in skeletal muscle oxidative capacityIn 2007, two different studies were published addressing whether a high fat diet (HFD) decreases or improves skeletal muscle mitochondrial oxidative capacity. In one (Garcia-Roves et al., 2007), rats were fed with a HFD during 4 weeks in order to raise circulating fatty acids and therefore to study the mechanisms that regulate the already reported improved fatty acid oxidation capacity of glycolytic skeletal muscle. Rats fed with the HFD regime showed higher fatty acids content, increased skeletal muscle fatty acid oxidative capacity in the epitrochlearis (glycolytic muscle), increased expression of enzymes of the fatty acid oxidation pathway and increased protein content of carboxylic acid cycle and OXPHOS system markers. Furthermore, this study showed that this metabolic adaptation occurs through activation of the peroxisome proliferated activated receptor delta (PPARdelta), a nuclear receptor responsible for regulating transcription of enzymes that belong to the fatty acid oxidation pathway and mitochondrial biogenesis process.
Fatty acids, mostly unsaturated, are ligands and activators of PPARs, which explain the metabolic regulations observed in this study (Garcia-Roves et al., 2007). Similar results were published, almost simultaneously, by Cooney and colleagues in mice (Turner et al., 2007). In both periods of time HFD mice showed an increased capacity to oxidize fatty acid in skeletal muscle, concomitantly with an increased enzymatic activity of key proteins in the fatty acid oxidation pathway and higher protein content of different mitochondrial markers. Most importantly, these improvements in fatty acid handling and mitochondrial respiration in fat-fed mice occurred at the time these animals showed skeletal muscle insulin resistance and impaired whole body glucose handling (Turner et al., 2007).

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