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. 2020 Aug;8(16):e14529.
doi: 10.14814/phy2.14529.

Human skeletal muscle metabolic responses to 6 days of high-fat overfeeding are associated with dietary n-3PUFA content and muscle oxidative capacity

Sophie L Wardle  1   2 , Lindsay S Macnaughton  1   3 , Chris McGlory  1   4 , Oliver C Witard  1   5 , James R Dick  6 , Philip D Whitfield  7 , Arny A Ferrando  8 , Robert R Wolfe  8 , Il-Young Kim  8 , D Lee Hamilton  1   9 , Colin N Moran  1 , Kevin D Tipton  1   10 , Stuart D R Galloway  1
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Human skeletal muscle metabolic responses to 6 days of high-fat overfeeding are associated with dietary n-3PUFA content and muscle oxidative capacity

Sophie L Wardle et al. Physiol Rep. 2020 Aug.

Abstract

Understanding human physiological responses to high-fat energy excess (HFEE) may help combat the development of metabolic disease. We aimed to investigate the impact of manipulating the n-3PUFA content of HFEE diets on whole-body and skeletal muscle markers of insulin sensitivity. Twenty healthy males were overfed (150% energy, 60% fat, 25% carbohydrate, 15% protein) for 6 d. One group (n = 10) received 10% of fat intake as n-3PUFA rich fish oil (HF-FO), and the other group consumed a mix of fats (HF-C). Oral glucose tolerance tests with stable isotope tracer infusions were conducted before, and following, HFEE, with muscle biopsies obtained in basal and insulin-stimulated states for measurement of membrane phospholipids, ceramides, mitochondrial enzyme activities, and PKB and AMPKα2 activity. Insulin sensitivity and glucose disposal did not change following HFEE, irrespective of group. Skeletal muscle ceramide content increased following HFEE (8.5 ± 1.2 to 12.1 ± 1.7 nmol/mg, p = .03), irrespective of group. No change in mitochondrial enzyme activity was observed following HFEE, but citrate synthase activity was inversely associated with the increase in the ceramide content (r=-0.52, p = .048). A time by group interaction was observed for PKB activity (p = .003), with increased activity following HFEE in HF-C (4.5 ± 13.0mU/mg) and decreased activity in HF-FO (-10.1 ± 20.7 mU/mg) following HFEE. Basal AMPKα2 activity increased in HF-FO (4.1 ± 0.6 to 5.3 ± 0.7mU/mg, p = .049), but did not change in HF-C (4.6 ± 0.7 to 3.8 ± 0.9mU/mg) following HFEE. We conclude that early skeletal muscle signaling responses to HFEE appear to be modified by dietary n-3PUFA content, but the potential impact on future development of metabolic disease needs exploring.

Keywords: exercise; fish oil; insulin resistance; omega-3; overfeeding; type 2 diabetes.

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Conflict of interest statement

The authors have no conflicts of interest. The Diabetes Research and Wellness Foundation supported the study with a grant to KDT, CM and SDRG. Fish oils were provided for the study by SMARTFISH Nutrition, Norway. SLW was supported by a University of Stirling funded PhD studentship.

Figures

Figure 1
Figure 1
(a) Study design; and (b) infusion trial schematic. Both groups (high‐fat control [HF‐C] and high‐fat fish oil [HF‐FO]) completed all aspects depicted, with the only difference between groups being the n‐3PUFA fat content provided in the experimental diet. The beverage ingested in the infusion trial was a standard 75 g glucose in 300 ml water.
Figure 2
Figure 2
(a) Serum insulin and (b) plasma glucose concentration during the oral glucose tolerance test conducted before (Pre‐HFEE) and after (Post‐HFEE) high‐fat energy excess in the high‐fat control (HF‐C) group. (c) Serum insulin and (d) plasma glucose concentration during the oral glucose tolerance test conducted before (Pre‐HFEE) and after (Post‐HFEE) high‐fat energy excess in the high‐fat fish oil (HF‐FO) group. No significant trial (pre‐ to post‐HFEE), or interaction (trial by group) effects were noted.
Figure 3
Figure 3
(a) Combined EPA, DPA, and DHA composition of whole blood pre‐ and post‐HFEE for both high‐fat control (HF‐C) and high‐fat fish oil (HF‐FO) groups (n = 10 per group); and (b) combined EPA, DPA and DHA composition of skeletal muscle phospholipid membrane fraction pre‐ and post‐HFEE for both HF‐C and HF‐FO groups (n = 9 per group). Data are expressed as median, 25th‐75th centile (box) and range (whiskers) and represent % of total fatty acids (FAs). ** significantly different p = .000002, and * significantly different p = .04, from pre‐HFEE in HF‐FO group only.
Figure 4
Figure 4
(a) Total skeletal muscle ceramide content pre‐ and post‐ 6 days of high‐fat energy excess (HFEE) in high‐fat control (HF‐C) and high‐fat fish oil (HF‐FO) conditions; (b) individual ceramide species, presented for HF‐C and HF‐FO groups, expressed as the fold‐change from pre‐ to post‐HFEE; and (c) association between muscle maximal citrate synthase activity measured before 6 days of high‐fat energy excess (HFEE) and the pre‐ to post‐HFEE absolute change in skeletal muscle total ceramide content (HF‐C and HF‐FO groups combined). Data are expressed as median, 25th‐75th centile (box) and range (whiskers). n = 9 per group. * significantly different from pre‐HFEE, p < .05.
Figure 5
Figure 5
(a) PKB activity in the basal (0 hr) and insulin stimulated states (2 hr) pre‐ and post‐ 6 days of high‐fat energy excess (HFEE) for both high‐fat control (HF‐C) and high‐fat fish oil (HF‐FO) groups; (b) Insulin‐stimulated change in PKB activity for HF‐C and HF‐FO, pre‐ and post‐HFEE; and (c) Basal skeletal muscle AMPKα2 activity pre‐ and post‐HFEE for both HF‐C and HF‐FO groups. Data are expressed as median, 25th‐75th centile (box) and range (whiskers). n = 9 per group. # group by time interaction (pre‐ to post‐HFEE) for PKB and AMPKα2 activity, p = .025 and p = .038, respectively. * AMPKα2 activity significantly higher at post‐HFEE compared to pre‐HFEE in HF‐FO group only (p = .049).
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