Mitochondrial Energetics in the Heart in Obesity-Related Diabetes

Abstract

OBJECTIVE-In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVO 2 ) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS-Oxygen consumptionand cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H 2 O 2 generation determined in isolated mitochondria.RESULTS-db/db hearts exhibited reduced cardiac function and increased MVO 2 . Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H 2 O 2 production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 ␣-subunit of ATP synthase was reduced.CONCLUSIONS-These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from ␤-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…Likewise, reduced mitochondrial respiration has been reported both in db/db mouse hearts (Boudina et al. 2007; Tocchetti et al. 2012) and ob/ob mouse hearts (Boudina et al.…”

“…A mitochondrial biogenic response (increased number, but somewhat smaller mitochondria) has been reported to occur in the db/db mouse heart aged 8–9 weeks (Boudina et al. 2007). However, at 18 weeks of age decreased mitochondrial size as well as decreased state 3 respiration rates were reported for subsarcolemmal mitochondria (Dabkowski et al.…”

“…This fatty acid oxidation‐dependent ROS generation may be a hallmark of T2DM and has been reported to occur in the heart (Boudina et al. 2007; Wang et al. 2015), skeletal muscle (Anderson et al.…”

“…2015) and in db/db mice (increased HNE‐modified proteins and increased malondialdehyde levels) (Boudina et al. 2007). It is important to note that in the healthy heart, HNE ‐an aldehyde derivative generated from lipid peroxidation‐ is readily metabolized by conjugation to glutathione (and subsequently removed by aldose reductase) or by oxidation to 4‐hydroxynonenoic acid by aldehyde dehydrogenase (Srivastava et al.…”

Cardiovascular consequences of obesity and targets for treatment

“…Lastly, increasing BMI is an independent predictor of increasing myocardial oxygen consumption and decreasing efficiency both in animal models and in a recent study in young obese women [58,66]. Decreased efficiency may contribute to impaired ATP production, thereby hindering cardiac function, and decreased efficiency is a hallmark of heart failure.…”