**5. Mitochondrial dysfunction in obesity**

upregulation of these pathways increases the expression of oncogenes and proteins involved in metastasis (e.g. matrix metalloproteinases) and in epithelial to mesenchymal transition [36]. Of note, oncogene activation has been reported to enhance mitochondrial ROS production, and

A vast body of literature covers the functional modifications of mitochondria under diabetic conditions. Because cardiovascular insults remain the leading cause of death for diabetic patients [38], most of the attention has been focused on the modifications occurring in cardiac mitochondria to provide a better rationale for the morphological and functional modifications observed in diabetic hearts. Further, the incidence and severity of cardiovascular complications are markedly increased in both male and female diabetic patients, with the latter exhibit-

In humans, our understanding of the disease is complicated by the presence of two pathological conditions: diabetes type 1, in which insulin production is lacking, and diabetes type 2, in which insulin is still produced, sometimes to a greater extent than under normal conditions, and yet it is not functionally efficient in controlling the glycemic state of the patient. An additional confounding parameter is that to a large extent type 2 diabetic patients are overweight

This variety of conditions is also reflected in the heterogeneity of animal experimental models utilized to investigate the disease. Also here, models of type 1 diabetes are conceptually simpler in that animals are injected with agents that damage pancreatic beta-cells and abolish insulin secretion, fully mimicking the human condition. Models for type 2 diabetes are more heterogeneous, spanning from genetically conditioned animals (KO animals for specific proteins, receptors, or signaling molecules) to genetically inbred animals (e.g. Koletsky rats), to animals that develop diabetes spontaneously, to animals fed assorted high fat diets with or without sucrose, and injected with subliminal doses of beta-cell damaging agents that limit but not completely abolish the endogenous production of insulin, or treated with various oral antidiabetic agents [40]. Because of this plethora of models, it is not simple to determine to which extent modifications of mitochondrial dehydrogenase are a primary or secondary

The development of diabetic cardiomyopathy has been etiologically attributed to several factors including metabolic [41], biochemical [42] and ultra-structural [43] modifications within the cardiac myocytes. Scrutiny of mitochondrial function in cardiac mitochondria from streptozotocin-treated rats has shown a decline in respiration and oxygen consumption, more pronounced for state 3 than state 4, which translates into a decrease in ATP production [44]. This energy deficiency has been considered a key factor in the development of diabetes-related cardiac dysfunctions, although changes in cardiac microvasculature [45], metabolic and hormonal disturbances [46] and concurring hyperglycemia [47] can certainly act as co-factors. Combining defective mitochondrial respiration with increased ROS formation, studies from our laboratory have indicated that succinate dehydrogenase [48] and pyruvate dehydrogenase [49] are highly sensitive to ROS-induced damage, forming stable, non-functional adducts

or obese, with an altered lipid status both in serum and within tissues (lipotoxicity).

insult in the pathogenesis of the diabetic condition and its complications.

ROS generation appears to be required for oncogene-mediated cell transformation [37].

**4. Mitochondrial dehydrogenases under diabetic conditions**

ing a greater incidence than the diabetic male counterparts [39].

132 Secondary Metabolites - Sources and Applications

The term obesity refers to a condition in which the amount of fat tissue in the body is increased to an excessive degree (i.e. more than 25% in body weight in men and more than 30% in women). The incidence of obesity or just overweight has been on the rising for the last several decades, and currently affects anywhere between 35 and 45% of the population, in developed and developing countries [50]. Obesity is the sixth most important risk factor, and the number of affected individuals has reached 2.1 billion worldwide, including 10% of all children. The main complications include particular forms of cancer (e.g. colon and breast cancer, in particular), type 2 diabetes mellitus, cardiovascular pathologies including stroke, and musculoskeletal dysfunctions, with a prohibitive price tag in terms of healthcare costs, morbidity and mortality [51]. Several reviews have addressed the changes in mitochondria functioning in obesity, and we refer to them for an in-depth understanding of the changes occurring in the organelle [52–53]. The emerging picture indicates that cardiac cells, adipocytes, skeletal muscle cells, beta-cells, liver cells and others are affected to a varying degree by lipotoxicity [54], which also affects mitochondria operation. Whether the dysfunction strictly depends on the abnormal presence of fatty acid in the cells and the biological membrane of the organelle, or other not-yet identified factors remains undefined. The most common mitochondrial dysfunctions associated with obesity have been identified in an abnormally low number of mitochondria with altered morphology, decreased expression of the F1-ATPase subunit, with consequent low ATP generation [53], higher expression of the uncoupling protein 2 (UCP2) [52] with associated increased production of O<sup>2</sup> − , ROS in general, and apoptosis [52]. At the same time, the abnormal presence of fatty acids and ceramide within the cell activate specific signaling that further impair the tissue response to insulin [53]. Due to the decline in number and the altered morphology of mitochondria, an unanswered question remains as to whether these modifications are secondary to intrinsic defects in mitochondrial dehydrogenases that link electron transport chain to TCA cycle and/or to proper ATP synthesis, or whether defects in mitochondria enzymes are consequence of defective synthesis of key components within the cell nucleus and defective import into already altered organelles.
