Overexpression of IMM UCP, UCP1, decreases weight gain in obesity-prone mice due to increased energy expenditure and reduced fatty acid synthesis. UCP1 expression can directly regulate fat deposition and contribute to obesity [46]. With age, PGC1α knockout (KO) mice show higher body weight and fat deposition in the liver, along with decreased mitochondrial oxidative capacity, whereas mice with even slightly elevated levels of PGC1α are resistant to age-related obesity [28, 47]. Mice with muscle-specific deletion of cytochrome c oxidase 10 (COX10) or mice expressing mutant Peo1 (a mitochondrial helicase) leads to development of a starvation-like response, along with an increase in fibroblast growth factor (FGF) 21, a metabolic hormone. This indicates that there can be noncell-autonomous effects of mitochondrial function on systemic metabolism [48]. Targeted disruption of Atg7, an autophagy gene in skeletal muscle, protects mice from diet-induced obesity and insulin resistance [49]. Interestingly, these effects of mitochondria are mediated in a noncell-autonomous manner through the mitokine FGF21 [50]. Removal of mitochondria through enhanced mitophagy could reduce mitochondrial numbers, resulting in decreased substrate oxidation, further enhancing lipid accumulation. Interestingly, it has been shown that treatment of rats with mitochondria-targeted antioxidant or overexpression of catalase to scavenge ROS completely preserves insulin sensitivity in spite of an HFD [26]. Mitochondrial complex IV activity is inhibited in white adipocytes of middle-aged mice, elucidating a possible molecular mechanism for age-dependent obesity. Moreover, this decrease in activity is enough to impair FAO and lead to obesity during aging. It is well established now that WAT expansion results in hypoxia inside the tissue due to poor oxygenation. This promotes HIF1α accumulation, which in turn exacerbates WAT growth through complex IV inhibition in a feed-forward loop. Accumulation of HIF1α could be promoted not only by hypoxia but also by intracellular ROS and lipid accumulation [51]. Dysfunction of mitochondria results in increased production of ROS, inflammation, and upregulated inflammatory cytokines, which mediate the reduction of endothelial nitric oxide synthase (eNOS) expression in adipocytes. This decreases NO production through inhibition of PGC1α and hampers beta oxidation of fatty acids in mitochondria, leading to lipid accumulation in adipocytes, eventually precipitating as abdominal obesity. Resultant obesity leads to release of free fatty acids, which damage various organs such as skeletal muscle, pancreas, and liver, leading to a further decrease in metabolic function of mitochondria, affecting glucose uptake, and decreasing insulin sensitivity. In addition, 12/15-lipoxygenase (LOX) may cause mitochondrial dysfunction through its metabolites such as 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE), which can cause mitochondrial degradation [45]. Further, fat-specific deletion of 12/15-LOX improves glucose metabolism and protects against obesity-mediated complications [52]. Overall, these findings emphasize that mitochondrial function often lies upstream of metabolic consequences.

Mitochondrial Genome Variations in Obesity Patients

Numerous studies have attempted to identify causal mutations that could explain the rising obesity epidemic. However, obesity is a very complex disorder, with a greater contribution of lifestyle and environment, so the search for such mutations has proved to be challenging. Amongst monogenic mutations, the most common ones were found in the leptin and melanocortin pathway in the central nervous system [53]. Although these mutations do cause obesity, hyperphagia, hyperglycemia, and hyperinsulinemia, the rates of occurrence of these in humans is very low and cannot account for the exponential rise in obesity over the past 2 decades. Human obesity usually results from a combined effect of multiple genes, environmental factors, and lifestyle. Offspring have been found to have higher BMI correlations with their mothers than with fathers [54–56]. This points to the mitochondrial genome’s contribution toward body weight as being at least a partially inherited trait from the mother. The location of the mitochondrial genome inside the mitochondrial matrix without a protective histone covering and limited repair mechanisms makes it 3–10 times more susceptible than nuclear DNA to oxidative modifications that accumulate over time [57].

An interesting finding has been that maternal diet-induced obesity in a mouse model is associated with alterations in mitochondrial activity such as increased membrane potential and ROS, changed mtDNA content and biogenesis, and decreased glutathione, resulting in a more oxidized environment in zygotes [58]. This increased state of oxidative stress in oocytes and zygotes during the periconceptual period was found to be detrimental in embryogenesis [59]. Mitochondria are involved in oocyte maturation, fertilization, and initiation/progression of embryo implantation [60]. Given mitochondria’s primary role as the cell’s “powerhouse,” they produce ATP by coupling nutrient oxidation with reduction of NADPH and FADH 2 . Consumption of a high energy-rich maternal diet has been shown to place mitochondria in a “positive energy balance” (high substrate with low ATP demand), thus perturbing mitochondrial metabolism in the oocyte and zygote.

Mitochondrial genome polymorphisms such as mtSNP, 8684C > T (T53I) in the mitochondrial ATP synthase subunit 6 gene (ATP6), 3497C > T (A64V) in the NADH dehydrogenase subunit 1 gene (ND1), and 1119T > C (472U > C) in the 12S rRNA gene have been found to be involved in the development of obesity syndrome. Several research groups have studied the associations of different mtSNPs with obesity in various human ethnic groups during the course of evolution. Mitochondrial SNPs—ND2, COX2, and ATP8—have been observed within genes encoding proteins of oxidative phosphorylation and electron transport in subhaplogroups of the Pima Indians. These were adaptations acquired for a more energy-efficient metabolism due to an adoption of a more restricted caloric intake when this population migrated to the desert. However, with time, migrated humans adopted a more sedentary lifestyle thus acquiring a positive energy balance with high calorie intake and low ATP demand. Today, these same mutations may potentially contribute to obesity. For example, UCP is a mitochondrial inner membrane protein that is a regulated proton channel. UCP can dissipate the proton gradient generated by NADH-powered pumping of protons from the mitochondrial matrix to the inner mitochondrial space. Polymorphisms in the UCP2 gene (rs660339 and rs659366) have been found to be associated with the risk of abdominal obesity and abnormal body fat distribution in the Spanish population. The UCP2 A55V variant was also found to be associated with obesity and related phenotypes in an aboriginal community in Taiwan. UCP1 variants, g.IVS4-208T > G SNP, was associated with obesity in Southern Italy in the severely obese population. MtDNA haplogroup X and two mtSNPs (mt4823 and mt8873) have been observed to be significant markers associated with reduced body fat mass. UCP3 gene shows an association with obesity phenotypes in Caucasian families. A common polymorphism in the promoter of the UCP2 gene is associated with obesity and an allele associated with obesity and hyperinsulinemia in north Indians. In another study, overexpression of the transgene hOGG1 in human 8-oxoguanine-DNA glycosylase 1 (hOGG1) transgenic (TG) mice led to increased oxidative damage of mtDNA and manifested in obesity and hepatosteatosis. MtDNA variant (cytosine to adenine) in NADH dehydrogenase subunit 2 was found to directly affect ROS production from complexes I and III, which will have implications in inflammation and weight gain [61]. Thus mitochondrial mutations, in conjunction with environmental cues and lifestyle choices, often result in obesity.