Docosahexaenoic acid affects insulin deficiency- and insulin resistance-induced alterations in cardiac mitochondria

Abstract

.-The effect of docosahexaenoic acid (DHA) intake on cardiac mitochondrial function was evaluated in permeabilized fibers in insulin deficiency and insulin resistance in rats. The insulin-deficient state was obtained by streptozotocin injection 2 mo before investigations. Insulin resistance was obtained by feeding a 62% fructose diet for 3 mo. DHA was incorporated in the diet to modify the fatty acid composition of cardiac membranes, including mitochondria. Insulin deficiency decreased mitochondrial creatine kinase (mi-CK) activity and mitochondrial sensitivity to ADP. DHA intake prevented these alterations. Moreover, the insulin-deficient state significantly decreased n-3 polyunsaturated fatty acids (PUFA) and slightly increased n-6 PUFA in both cardiac and mitochondrial membranes, inducing a significant increase in the n-6-to-n-3 ratio. DHA intake maintained high myocardial and mitochondrial DHA content. Insulin deficiency also decreased glutamate-and palmitoylcarnitine-supported mitochondrial respiration, but DHA intake did not prevent these effects. In contrast, insulin resistance did not affect mi-CK activity or sensitivity to ADP. However, insulin resistance influenced the myocardial fatty acid composition with decreased n-6 and n-3 PUFA contents and increased monounsaturated fatty acid content. Only slight alterations were observed in mitochondrial fatty acid composition, and they were corrected by DHA intake. Moreover, insulin resistance decreased the glutamatesupported respiration, and DHA intake did not influence this effect. In conclusion, the impairment of cardiac mitochondrial function was more pronounced in the insulin-deficient state than in insulin resistance. The modification of fatty acid composition of cardiac and mitochondrial membranes by DHA partially prevented the mitochondrial alterations induced in the two models. mitochondrial respiration; myocardium; polyunsaturated fatty acid DIABETES IS ASSOCIATED WITH high cardiovascular morbidity and mortality, and both insulin-deficient and insulin-resistant diabetes induce biochemical and physiological changes in the heart (15). Animal studies have demonstrated a number of diabetes-induced changes in the diabetic heart, including changes in mitochondrial function (14) and fatty acid composition of heart membrane phospholipids. In uncontrolled diabetes, myocardial glucose utilization is markedly reduced, causing fatty acids to support a greater portion of total energy metabolism (23). Moreover, when diabetic rat hearts are perfused in the absence of fatty acids, glucose oxidation represents Ͻ20% of the ATP synthesis (14), suggesting an alteration of the fatty acid uptake regulation in mitochondria. In the diabetic heart, the level of malonyl-CoA, the physiological inhibitor of carnitine palmitoyltransferase I, seems to be reduced. In streptozotocin (STZ) diabetic rats, the activity of acetyl-CoA carboxylase, which produces malonyl-CoA, was shown to decrease (14). In the same model, Sakamoto et al. (24) reported an increase in malonyl-CoA decarboxy...

Eicosapentaenoic acid, but not oleic acid, stimulates β‐oxidation in adipocytes

“…As shown in Figure 3, exogenous EPA was incorporated into mitochondrial membrane lipids with a simultaneous decrease in palmitoleic acid (16:1). These changes in the mitochondrial membrane lipids are expected to alter membrane structure and cell functions (2,11), as we also confirmed (Fig. 1A, 1B).…”

“…Both EPA and DHA activate peroxisome proliferator-activated receptor α (PPARα), the nuclear transcription factor that regulates the expression of key enzymes in the control of FA β-oxidation in mitochondria and peroxisomes (6). EPA has been shown to induce mitochondrial FA oxidation and contribute to lipid-lowering effects (7), whereas the effects of DHA are still debatable (7,11). In hepatocytes, EPA increases the expression of carnitine palmitoyl transferase 1 (CPT-1), which increases the flux of FA toward mitochondrial β-oxidation and reduces the substrates for lipid synthesis and lipoprotein secretion.…”

Effects of Dietary Polyunsaturated Fatty Acids on Mitochondria

“…Ageing and insulin-deficiency are associated with fewer n-3 PUFAs and more n-6 PUFAs in mitochondrial membranes [26,[28][29][30][31]. As already described, feeding n-3 PUFAs restored age-associated changes in mitochondrial membrane composition.…”

“…Similarly, the n-6 to n-3 PUFA ratio was increased in diabetic animals [31]. These changes can, however, be reversed or exaggerated in rats with n-3 or n-6-rich diets [26].…”

A 9-wk docosahexaenoic acid-enriched supplementation improves endurance exercise capacity and skeletal muscle mitochondrial function in adult rats

“…Although we did not analyze mitochondrial membrane composition, it could have been altered by DHA supplementation, as it was in red blood cell and muscle cell membranes with a lower n-6/n-3 ratio. Indeed, membrane composition alterations are usually consistent in all cellular compartments, including cell membrane and mitochondrial membrane (46,61).…”