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. 2013 Jun 15;304(12):E1391-403.
doi: 10.1152/ajpendo.00584.2012. Epub 2013 Apr 30.

Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet

Ian R Lanza  1 , Agnieszka Blachnio-Zabielska, Matthew L Johnson, Jill M Schimke, Daniel R Jakaitis, Nathan K Lebrasseur, Michael D Jensen, K Sreekumaran Nair, Piotr Zabielski
Affiliations

Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet

Ian R Lanza et al. Am J Physiol Endocrinol Metab. .

Erratum in

  • Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E1048

Abstract

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) enhance insulin sensitivity and glucose homeostasis in rodent models of insulin resistance. These beneficial effects have been linked with anti-inflammatory properties, but emerging data suggest that the mechanisms may also converge on mitochondria. We evaluated the influence of dietary n-3 PUFAs on mitochondrial physiology and muscle lipid metabolites in the context of high-fat diet (HFD) in mice. Mice were fed control diets (10% fat), HFD (60% fat), or HFD with fish oil (HFD+FO, 3.4% kcal from n-3 PUFAs) for 10 wk. Body mass and fat mass increased similarly in HFD and HFD+FO, but n-3 PUFAs attenuated the glucose intolerance that developed with HFD and increased expression of genes that regulate glucose metabolism in skeletal muscle. Despite similar muscle triglyceride levels in HFD and HFD+FO, long-chain acyl-CoAs and ceramides were lower in the presence of fish oil. Mitochondrial abundance and oxidative capacity were similarly increased in HFD and HFD+FO compared with controls. Hydrogen peroxide production was similarly elevated in HFD and HFD+FO in isolated mitochondria but not in permeabilized muscle fibers, likely due to increased activity and expression of catalase. These results support a hypothesis that n-3 PUFAs protect glucose tolerance, in part by preventing the accumulation of bioactive lipid mediators that interfere with insulin action. Furthermore, the respiratory function of skeletal muscle mitochondria does not appear to be a major factor in sphingolipid accumulation, glucose intolerance, or the protective effects of n-3 PUFAs.

Keywords: ceramide; essential fatty acids; fish oil; high-fat diet; insulin sensitivity; long-chain acyl-coenzyme A; mitochondria; omega-3 fatty acids; polyunsaturated fatty acids; sphingolipid.

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Figures

Fig. 1.
Fig. 1.
Ten weeks of high-fat diet (HFD) increases body mass and fat mass in mice with or without fish oil. Body mass (A), fat mass (B), lean mass (C), and percent body fat (D) were measured by EchoMRI at baseline and after 5 and 10 wk of dietary intervention. Respiratory exchange ratio (RER; F) was derived from V̇o2 and V̇co2 measured by indirect calorimetry. Metabolic rate (G) was calculated from V̇o2 and RER. Food intake (E) was measured during calorimetry experiments. Total cage activity counts (H), ambulatory activity (I), and rearing activity (J) were measured by photocell beam breaks during calorimetry measurements. Bars represent means ± SE for normal-fat diet (NFD), HFD, and HFD with fish oil (HFD+FO). *Significant statistical differences from NFD (P < 0.05, Tukey's HSD).
Fig. 2.
Fig. 2.
Fish oil prevents decline in glucose tolerance with Hfd. Blood glucose measured over 2 h following an oral glucose bolus at baseline (A), 5 wk of diet (D), and 10 wk of diet (G). Glucose responses were quantified from the area above baseline (AAB) at baseline (B), 5 wk (E), and 10 wk of diet (H). Plasma insulin was measured in the fasted state and 15 min following glucose bolus at baseline (C), 5 wk (F), and 10 wk (I). Gene transcript levels (J) of glucose transporter type 4 (GLUT4), glycogen synthase-1 (GYS1), and insulin receptor substrate 1 (IRS1) were measured in muscle tissue at 10 wk. Bars represent means ± SE for NFD, HFD, and HFD+FO. *Significant statistical differences from NFD; #significantly different from HFD (P < 0.05, Tukey's HSD).
Fig. 3.
Fig. 3.
Mitochondrial abundance is increased with fish oil by electron microscopy with no change in mitochondrial DNA copy number. A, B, C: representative transmission electron micrographs (×25,000 magnification) of skeletal muscle from NFD (A), HFD (B), and HFD+FO (C) mice. D: average perimeter, width, height, and area of mitochondria were measured from digitized image. E: mitochondrial density by area was determined from digitized electron micrographs. F: mitochondrial DNA abundance was measured by RT-PCR using mitochondrial-encoded NADH dehydrogenase subunits 1 (ND1) and 4 (ND4) expressed relative to 28S as a nuclear housekeeping gene. G: gene transcript levels of peroxisome proliferator-activated receptor-α (PPARα), PPARγ (PPARγ), PPARγ coactivator 1α (PGC1α), nuclear respiratory factor 1 (NRF1), and transcription factor A, mitochondria (TFAM) were measured in muscle tissue at 10 wk. Bars represent means ± SE for NFD, HFD, and HFD+FO. *Significant statistical differences from NFD; #significantly different from HFD (P < 0.05, Tukey's HSD).
Fig. 4.
Fig. 4.
HFD increases mitochondrial respiratory capacity with no effect of fish oil. Respiration rates were measured in isolated mitochondria from skeletal muscle with substrates targeting complex I (CI), complex I+II (CI+II), and complex II (CII) (A) as well as lipid-based substrates (B). Nonmitochondrial V̇o2 was measured in the presence of antimycin A. Respiration rates were expressed per tissue wet (A and B) and mitochondrial protein content (C and D). Respiratory control ratio (RCR; state 3/state 4; E) and phosphorylation efficiency (ADP:O; F) were measured in isolated mitochondria. Bars represent means ± SE for NFD, HFD, and HFD+FO. *Significant statistical differences from NFD; #significantly different from HFD (P < 0.05, Tukey's HSD).
Fig. 5.
Fig. 5.
Hfd increases mitochondrial H2O2 production and catalase activity with no effect of fish oil. H2O2 production was measured in isolated mitochondria under state 4 conditions by spectrofluorometer, expressed relative to tissue wet weight (A) and relative to mitochondrial protein content (B). H2O2 emission was measured in permeabilized muscle fibers during a stepwise increase in succinate under state 4 conditions. Gene transcript levels (D) of superoxide dismutase-1 (SOD1), superoxide dismutase-2 (SOD2), catalase (CAT), and glutathione peroxidase (GPX1) were measured in muscle tissue at 10 wk. Activity of catalase (E) and total SOD (F) were measured spectrophotometrically. Skeletal muscle oxidative damage (G) was determined from 8-oxo-2′-deoxyguanosine (8-oxo-dG), a major product of DNA oxidation measured by mass spectrometry. Bars represent means ± SE for NFD, HFD, and HFD+FO. *Significant statistical differences from NFD; #significantly different from HFD (P < 0.05, Tukey's HSD).
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