1.7 Obesity
1.7.5 Mitochondrial dysfunction in obesity and T2DM
Skeletal muscle metabolism and mitochondrial function are also impaired in obesity. Skeletal muscle from obese people exhibits increased fatty acid uptake, lipid accumulation and oxidative stress (450;451). Fatty acids are degraded within cells to diacyglycerol and ceramide, which are associated with impaired insulin sensitivity in this tissue (452;453). One of the contributing factors in lipid accumulation and oxidative stress is the reduction of fatty acid (FA) oxidation in obesity and T2DM (454;455). However, later studies have demonstrated that FA oxidation is either moderately increased or not different compared to lean controls in both rodent and human studies (456;457). The differences in mitochondrial oxidation in different studies may be due to the differences in
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cellular mitochondrial content (456;458). Studies comparing skeletal muscle mitochondrial content of obese and T2DM vs lean individuals show it to be reduced in both obese and T2DM patients (459) i.e. reduced mitochondrial mass may be responsible for mitochondrial dysfunction. Similarly levels of
mitochondrial proteins and their genes are also reduced in skeletal muscle in obesity and T2DM (460;461).
Apart from reduction in oxidation, FA oxidation is incomplete in obesity (462), and also after having a high fat diet in obese rodents and humans (462-464). Incomplete FA oxidation is associated with accumulation of by-products of metabolism, namely acylcarnitines and other short chain fatty acids which are proposed to cause mitochondrial dysfunction and insulin resistance (463;464). Moreover the activity of ETC in mitochondria is also reduced in obese individuals with T2DM as compared to lean controls (459).
Type II glycolytic fibres have a reduced capacity to oxidise fat (465) and to counter oxidative stress (466), and possibly contribute to increased oxidative stress. In the skeletal muscles of individuals with diabetes, type IIx glycolytic fibre expression is higher (467). Similarly the weight gain response to
overfeeding is associated with type IIa fibre expression (468). Fibre type expression may play an important role in skeletal muscle function and weight loss success in obesity.
Mitochondrial morphology is also changed in obesity and T2DM. Higher rates of mitochondrial fission are implicated in the development of diabetic neuropathy (469;470). In fasting and stress conditions mitochondria are elongated, whereas obesity and high fed state is associated with shorter and rounder mitochondria. In addition increases in mitochondrial fission proteins dynamin-related protein 1 and fission protein 1 have been observed in the skeletal muscle of ob/ob and high-fat fed mice, and palmitate-treated C2C12 cells (471). Smaller, rounded mitochondria and a fragmented mitochondrial network are associated with a reduction of the fusion protein, mitofusin-1 in skeletal muscle of obese rodents and humans (472). In addition, lower levels of the fusion proteins mitofusin 1 and optic atrophy 1 have also been observed in the individuals with T2DM (473).
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Lower mitochondrial capacity in obesity and T2DM is not irreversible as mitochondrial capacity can be restored. Due to the hypothesis that
mitochondrial dysfunction could be secondary to excess lipid accumulation in skeletal muscle, weight loss was initially tested as a strategy but with negative results (474). Toledo et al. compared the relative contribution of weight loss versus weight loss combined with exercise training. They showed that both groups experienced a comparable degree of weight and fat mass loss along with improvement in insulin sensitivity. However, improvement in mitochondrial content and ETC activity was only observed in the combined training group (475). Others have also shown improvement of mitochondrial content and activity with exercise training in insulin-resistant subjects with and without T2DM (476;477). These effects of exercise are not triggered by amelioration of the insulin resistant state or a reduction in intra myocellular lipid content, but are more likely due to an increase in contractile activity induced by exercise (474).
1.7.5.1 Mitochondrial dysfunction in atherosclerosis
Atherosclerosis begins with the recruitment of inflammatory cells to the intima and endothelial dysfunction is frequently involved in atherosclerosis (see Section 1.2.2). Elevation of endothelial mitochondrial ROS (mROS) initially leads to endothelial dysfunction and apoptosis and later enhanced inflammation – a dominant feature of atherosclerosis. Moreover EC are more sensitive to ROS as compared to VSMC (33). The increase in mROS is in response to many
atherosclerosis inducers, including hypertension, hyperglycemia, ox-LDL and TG. For example, exposure of ECs to free fatty acids, levels of which are upregulated in patients with metabolic syndrome, increases mROS (478;479).
In samples from human atherosclerotic plaque , mitochondrial DNA damage is increased, probably because of proximity to the electron transport chain and the relative lack of mtDNA repair mechanisms (32). The resulting mitochondrial mutations may lead to increased production of ROS and may initiate a cycle of positive feedback. Increased DNA damage and failure of DNA repair cause defects in cell proliferation, apoptosis, and mitochondrial dysfunction which concomitantly lead to ketosis, hyperlipidemia, and increased fat storage further promoting atherosclerosis and the metabolic syndrome. Recently Yu et al.
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showed that mitochondrial DNA damage can promote atherosclerosis independently of ROS, through its effects on VSMC and monocytes and is associated with higher risk plaques in human (34).
In summary, mitochondrial dysfunction is involved in atherosclerosis by impairing endothelial function but its independent role in atherosclerosis still needs to be evaluated.
Figure 1.7 Proposed relationship between mitochondrial dysfunction, endothelial dysfunction and hypertension. Adapted from Tang et al 2014 (24).