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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., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

DNA methylation is modifiable by acute and chronic exercise. DNA methyltransferases (DNMT) catalyze this process; however, there is a lack of literature concerning the specific mechanisms by which exercise-induced modifications occur. Interleukin 6 (IL-6) stimulation of various cell lines has been shown to augment DNMT expression and nuclear translocation, which suggests a possible pathway by which exercise is able to elicit changes in epigenetic enzymes. The present study sought to elucidate the response of the de novo methyltransferases DNMT3A and DNMT3B to circulatory factors found in plasma isolated from whole blood before and after 120-min of treadmill running at an intensity of 60% of individual velocity at V˙O2max (vV˙O2max) interspersed with 30-sec sprints at 90% of vV˙O2max every 10-min. Peripheral blood mononuclear cells (PBMCs) isolated from a resting participant were incubated with plasma isolated from exercising participants (n = 10) or recombinant IL-6 (rIL-6), followed by nuclear protein extraction and quantification of DNMT3A and DNMT3B concentrations. Nuclear concentrations of DNMT3B significantly decreased following the experimental protocol (P = 0.03), with no change observed in DNMT3A (P = 0.514).Various concentrations of rIL-6 caused an elevation in both DNMT3A and DNMT3B nuclear concentration compared with the blank control. The conflicting results between exercising and rIL-6 conditions suggests that IL-6 does regulate DNMT nuclear transport, however, other plasma mediators may also exert significant influence on the nuclear concentrations of these enzymes., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)