In times where the prevalence of obesity increases steadily and has become one of the so called “top killers” of the world, it is necessary to understand more how obesity affects our body and more importantly why it affects our body in that manner. To do that this article will emphasize on the bidirectional relationship between obesity and mitochondrial dysfunction. Overall said it appears that in patients suffering from obesity the total number of mitochondria seems to decrease in the different tissues due to an increase in production of the Tumor necrosis factor alpha (TNFa), which stimulates the extrinsic apoptotic pathway. However, it is of high importance to notice that the effects of obesity differ from tissue to tissue (as discussed later). Likewise, the production of Reactive Oxygen Species (ROS) inside the mitochondria, seems to increase also. This increase in ROS is often also associated with damage of the mitochondrial DNA (mtDNA) leading to mutations that may affect important metabolic pathways in the human body. Following mutations in the mitochondrial DNA can also be inherited in a maternal fashion and can lead to metabolic disorders like diabetes. Moreover, it is important to mention that the effects of obesity will also differ from woman to men, because of hormonal reasons that cause different fat deposits in men (more visceral fat) compared to women, that tend to have higher fat deposits at gluteal and femoral subcutaneous regions. On the other hand, there is also a lot of evidence that supports the thesis of mitochondrial dysfunction leading to obesity. For example, in elderly people the volume of mtDNA decreases and may result also in metabolic changes. To conclude, this article gives some possible ideas on how mitochondrial dysfunction could be treated.
Obesity is referred as a medical condition involving excessive accumulation of adipose tissue in the body with a consequent elevated body mass index (BMI) [1]. It is a complex disease that presents a risk to health, since it increases the danger of contract certain diseases such as various Cardiovascular Diseases, Type 2 Diabetes, Sleep Apnea and Depression. Obese people can suffer from excess of fat, which is named adipose tissue. There are two main types of adipose tissue: White Adipose Tissue (WAT) that appears yellow and Brown Adipose Tissue (BAT) that appear “brownish” due to a more elevated number of mitochondria inside it in light microscopy. The role of the White Adipose Tissue is principally to store energy, while the Brown Adipose Tissue is mainly for energy expenditure [2]. The high caloric diet that is nowadays available in more civilized countries and a nutritional transition to processed foods, have become a major health risk, since many countries have witnessed a 2-fold or even 3-ford increase to the incidence of this disorder compared to 30 years ago [1].
Furthermore, other external aspects have been influencing this increase in the rate of incidence, such as more sedentary lifestyles, economic growth, industrialization and mechanized transport [3,4]. According to a study, in 2015-2016, the prevalence of obesity among adults (~40%) was higher than in youth (~20%) and higher among middle aged adults (~43%) rather than younger ones (~36%). A recent study in 2017 showed that the average prevalence of obesity is 31% and is associated with a double increase in the risk of coronary heart disease and a 1.5-fold increase in the risk of all-cause mortality [5]. Obesity is a clinical case that might be consequence of several different factors, one of these can be a defect in cells’ mitochondria, a mitochondrial dysfunction.
Carl Brenda (1898) was the first to introduce the term “mitochondrion” to humanity. Mitochondrion stands for the greek words “mitos” (thread) and “chondros” (granule) [6]. The mitochondrion is a cell organelle whose function is the cells are known as the powerhouse since most of the metabolic pathways that produce energy occur inside it. Mitochondria are found floating in the cytoplasm of the cell and their number varies depending on cell type, function and energy requirement. Their structure is composed of an outer membrane, an inner membrane that folds the internal part, called matrix, creating structures called cristae. Mitochondria are filled with water and proteins, called enzymes, that catalyze (speed up) the metabolic reactions. Many important reactions are taking place at this organelle such as the Citric Acid Cycle (Krebs Cycle), the Fatty Acid Oxidation (β
More detailed the Fatty acids once are broken down to Acyl-Coenzyme A (Acyl-CoA) are traveling through the carnitine pathway in the mitochondrial matrix and entering the Krebs Cycle. Glycolysis, that converts Glucose to Pyruvate, has the same “ending titles” since Pyruvate is converted to Acetyl-CoA and enters the Krebs Cycle as well. Many Amino Acids enter the Krebs Cycle too and the end products of the Krebs Cycle are Nicotinamide Adenine Dinucleotide (NADH), Flavin Adenine Dinucleotide (FADH2) and Guanine Triphosphate (GTP). However, our cells need Adenosine Triphosphate (ATP), so those three products have to undergo the Electron Transport Chain (ETC) and convert to ATP. The ETC is composed by five complexes that use H2O and two electron transporters to convert the redox active coenzymes to ATP. If there is a decrease in O2 availability, there will be an activation of transcriptional responses to preserve tissue O2 supply and increase glycolytic activity. This results in the production of Reactive Oxygen Species (ROS) in Complex III of the ETC in mitochondria, leading to high levels of mitochondrial mutations and other alternations [10].
Mitochondria have their own DNA that has prokaryotic nature since it is circular, covalently closed and double stranded. The mitochondrial genome (mtDNA) is maternally inherited and has high possibility to be mutated because of the inability of the Polymerase γ to repair the possible mutations and the exposure to ROS. In the past 30 years more than 250 mtDNA mutations have been classified and only recently it has been possible to estimate a rate of incidence to mitochondrial disorders, which is approximately, in adults, 12.5 every 100.000 individuals, and one in 4300 people carries mitochondrial mutations [11].
Mitochondrial Dysfunction can be caused by different pathways, substances such as ROS, and conditions such as Obesity. All three can be related to each other since the human metabolic pathways do not happen through one way, but through many different ways. Following there are three different pathways, through which is believed that Obesity can affect mitochondrial function.
Obesity and high fat diet can cause mitochondrial dysfunction due to reduction of the mitochondrial numbers because of an increase in Tumor Necrosis Factor alpha (TNFa), that will lead to Caspase 8 activation and release of the Cytochrome C causing apoptosis [12]. However, in astrocytes TNFa enhances the expression of Intracellular Adhesion Molecule 1 (ICAM1) and Major Histocompatibility Complex class II (MHC class II) [13]. Alternations of the mitochondrial genome is another reason for the decrease in mitochondrial size and structure. Also, Enzymatic oxidative Capacity, since the level of mitochondrial biogenesis will be reduced
Although mitochondria are in low-abundant levels in WAT, they play a crucial role in their metabolic pathways, implying that any mutation can affect them. During adipose tissue differentiation mitochondria number and activity increase. The ROS levels though, as well as the duration of their generation are important for the initiation either of a physiological or pathological response [18,19,20,21]. An experiment in the WAT of obese ob/ob mice reported that mtDNA was reduced. However, according to Dahlaman et al. (2006), obesity is not the main cause of mtDNA alternations, but diabetes [22].
In humans the control of fat distribution is determined by sex hormones. In general, men have less total body fat that is located mostly on the intra-abdominal region, whereas women have more total body fat that is located mostly in the gluteal and femoral subcutaneous regions. It is noticed that the fat distribution can differ in post- and premenopausal women [23,24]. According to some studies Estrogen plays a crucial role in the distribution of fat in menopausal women. However, other studies conclude that the reasons for increasing obesity in menopausal women are not clear. The decrease in Estrogen levels during the climacteric phase of women, is associated with an increase on the abdominal fat, as well as a decrease of the subcutaneous fat [25].
The role of mitochondria in the metabolic pathways, as mentioned earlier is essential; hence any dysfunction of this organelle may lead to metabolic syndromes such as obesity. It is a bidirectional pathway, but mitochondrial dysfunction is to be affected by different factors that are associated to Obesity.
Changes elicited by the process of ageing include alterations in the process of mitochondrial respiration, changes in the mtDNA, alterations in structure and a lower ATP production [33,34,35,36]. These facts were underlined in study results from animal experiments and cell cultures, which results also added the fact that middle aged mitochondria showed an increase in activity, whereas old mitochondria showed a more depressed activity [37]. This increase in mitochondrial activity however is to compensate the reduction in mitochondrial efficiency, but on the other hand results in a further increase in ROS production. This foster further age-related mitochondrial dysfunctions, that can lead to further disease patterns such as obesity or diabetes Typ 2 [38,39]. However, a trail called the CALERIE reported that physical activity conjoined with calorie restriction seemed to increase the oxidative capacity of skeletal muscle and reduce the risk of cardiovascular disease by approximately 38% compared to the control group, by increasing the lifetime of mitochondria [40,41].
In addition to this, some other studies showed that different pharmacological impacts, including the drugs aspirin and metformin, which seemed also to increase the long-life ability of the mitochondria [42,43,44]. Many anti-ageing studies do not provide enough follow ups to fully validate the results. Also it is important to notice that the results of the CLAERIE study only included previously non obese survey participants,which makes it difficult to transfer those results to other population groups such as already obese people. For the pharmacological therapies, it is important to notice that the time the drug intervention is started and also the selection of survey participants may be crucial for the test results. However, all in all, it can be stated that ageing of mitochondria seems to play a very important role in causing mitochondrial dysfunctions and its associated diseases.
Considering that mtDNA is inherited by the mother, mutations in mtDNA can be transmitted from the mother to her children. Mitochondrial DNA mutations can lead to Diabetes Mellitus (DM) that can be associated with other defects such as deafness [45]. In one experiment with 130 patients diagnosed with DM, family history of DM and 3 unrelated patients with mtDNA were screened using genetic diagnostic methods. First degree relatives, of the 3 patients with mtDNA mutation, had this specific mutation also observed. From those patients, most mothers had DM and some of them had sensory hearing loss. In addition to this study, another study concluded that mtDNA mutations of the mother can lead to maternally inherited diabetes and deafness and can be identified through mtDNA testing [46]. This suggests that mtDNA mutations causing diabetes, which can cause obesity, can be inherited maternally [47].
However, those mitochondrial mutations can be age-related changes that can mediate apoptosis and cause ROS induce damage. By the development of the mtDNA mutator mouse, with mutated mtDNA polymerase γ, a study showed that mtDNA mutations can be caused by ageing (as discussed before). Age related changes may lead to atherogenesis and maybe also diabetes [48]. All in all, maternally inherited mutations of mtDNA, ageing that causes mitochondrial dysfunction, deficiency of Estrogens in menopausal women and excess of fat can lead to mitochondrial dysfunction. This dysfunction can affect different organs and tissues of the human body.
In skeletal muscle excess of fat and especially excess of palmitic acid (PA), leads to mitochondrial fragmentation that is associated with the high levels of oxidative stress, low levels of ATP production and reduce glucose uptake stimulated by insulin [49].
In BAT, defects in fatty acid oxidation and abnormal glucose homeostasis due to mitochondrial dysfunction can lead to impaired thermogenesis. Additionally, in patients with specific mtDNA mutation following by mitochondrial dysfunctions, multiple symmetrical lipomatosis was observed [57]. However, evidence from other studies have shown that mitochondrial activation in BAT is an efficient treatment for obesity prevention by energy expenditure, in alternative to drug therapy and surgery. Although recent studies in mice suggest that, WAT browning is a valid alternative to BAT thermogenesis and can result in resistance to diet-induced obesity and an improvement in metabolism [58], other studies reported that exposure to cold temperatures accelerates plasma lipid dispersion by triglyceride absorption into BAT, resulting into an enhance in dyslipidemia [59]. In addition to that, substances used to imitate the function of activated UCP1 (specialized uncoupling protein in BAT mitochondria), if exceeded, involves side effects such as hyperthermia and even death [60,61,62].
The effect of mitochondrial dysfunction in the heart is also perceivable. The heart has lots of mitochondria; hence is very vulnerable. As mentioned before, mitochondrial defects can disrupt signaling pathways and protein interactions, leading to increase production of ROS, which can cause cardiac senescence [63]. It is not clear yet, whereas, the mitochondrial dysfunction in the cardiac cells is related to ageing, but obesity can affect mitochondrial function, and this implies also to the heart, since it can cause cardiac failure [64]. Another research states that, the size and appearance of cardiac mitochondria, as well as, the mitochondrial dynamics is not as revealing as the proteins involved in regulating the fusion of cardiac mitochondria [65].
A study in high-fat diet mice showed an abnormal mitochondria density and morphology, abnormal expression of genes that are involved in mitochondrial dynamics, decreased mtDNA replication, low levels of Complex I-III and Citrate Synthase activity, as well as, decrease in mitochondrial respiration. Those findings showed a significant correlation to the fat deposition in the myocardium, and the cardiac hypertrophy and dysfunction that were observed in those mice [66,67]. The same study shows that mitochondrial dysfunction and heart failure can be caused by a chronic exposure to excesses of fatty acids [68]. However, this study was just performed with 40 male rates over a period of 28 weeks [66]. Evidence suggests that there are sex-specific differences between ventricular myocytes in older men and women, which affects the heat failure rate associated with reduced ejection fraction [66]. Moreover, another study confirms that the accumulation of fatty acid is not only a cause of cardiac dysfunction, including heart failure but is also a consequence of it [69].
Additionally, another study shows that a mtDNA mutation at position nt. 4300 of the tRNA gene is associated with hypertrophic cardiomyopathy [70]. Hypertrophic cardiomyopathy is the thickening of the ventricles’ walls, which can block the blood flow out of the ventricle leading to even cardiac arrest [71]. Although this disease is heterogeneous, mitochondrial defects inherited by the mother should be considered in differential diagnosis according to Cascli et al.
As mentioned earlier, mitochondrial dysfunction can be involved in many diseases, for example cardiac and skeletal myopathies, obesity and diabetes mellitus. One of the best ways to avoid those effects is exercise [72]. Endurance training, for example, improves the ETC activity, whereas resistance training can lead to a reduction of mutated mtDNA by stimulating the incorporation of satellite cells, which have low levels of mutated mtDNA, into existing muscle fibers. Another benefit is the increase in mitochondrial proliferation [69,70]. This theory is supported by another research that states that exercise can improve mitochondrial function while reduction mitochondrial inflammation [73].
But there are also different theories for treatments specific for cardiac malfunction. For example, one study states that, an mitochondria-targeted antioxidant would be a good option for treating a heart disease because the heart is sensitive to oxidative stress caused by the generation of ROS [74]. Another study suggests that, implanting autologously derived mitochondria helps with ischemia-reperfusion injury by enhancing the oxygen consumption, high-energy phosphate synthesis and the proteomic pathways, which is important for the post-infarct cardiac function [75].
Furthermore, Estrogen plays an important role in the development of obesity, studies have shown that Estrogen Therapy is beneficial in menopausal women, since it decreases visceral adipose tissue, fasting glucose serum and insulin levels [76,77].
Lastly, low-carbohydrate diet especially in diabetic patients is significant. Usually diabetic people can be treated with sulfonylurea and insulin. Also, some articles suggest that nitric oxide (NO) deficiency is significant in mitochondrial dysfunction in diabetic patients. The amino acids Arginine and Citrulline can be used as a supplement because they act as NO precursors. However, this treatment is still “unofficial” for diabetic-obese people, but doctors apply it to patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELA) [80].
All in all, there is still absence of therapeutic measures for mitochondrial disorders. A lot of research needs to be done to give more and diverse treatment for the multifaceted mitochondrial dysfunctions [81].
Mitochondrial dysfunctions and obesity are in very close association with each other (bidirectional). On one hand mitochondrial dysfunction can lead to obesity by the before mentioned pathway of ageing and maternally inherited mutations in the different tissues of the human body (e.g. heart, BAT or skeletal muscle). On the other hand, obesity can also cause mitochondrial dysfunction through the extrinsic apoptotic pathway, due to genetical alterations caused by an increase of ROS levels or the influence of Estrogen levels.
All in all, even though there is an association between obesity and mitochondrial dysfunction, more research is needed to better describe the exact Pathway of both, obesity causing mitochondrial dysfunction and the other way around.
The authors have nothing to disclose.
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