PMC

Myriocin treatment reverses the impairment in aerobic exercise capacity caused by DIO. Time (A) and distance (B) during an exercise capacity challenge on a running treadmill. Values represent mean ± SE (n = 8–12). Differences were determined using a two-way ANOVA followed by a Bonferroni post hoc analysis. *P < 0.05, significantly different from the low-fat diet counterpart.

Substrate preference in lean and obese mice. Twenty-four-hour (A), dark cycle (B), and light cycle respiratory exchange ratio (C) in low-fat–fed and obese insulin-resistant mice treated with either vehicle control or myriocin. Values represent mean ± SE (n = 8–12). Differences were determined using a two-way ANOVA followed by a Bonferroni post hoc analysis. *P < 0.05, significantly different from the low-fat diet counterpart.

Malonyl CoA decarboxylase-deficient mice (MCD−/−) do not accumulate skeletal muscle ceramide after 12 weeks of high-fat feeding. A: Area under the curve during a glucose tolerance test after 12 weeks of high-fat feeding in wild-type and MCD−/− mice. B: Corresponding gastrocnemius ceramide levels in MCD−/− mice after 12 weeks of high-fat feeding. Values represent mean ± SE (n = 5–8). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from low-fat diet counterpart. †P < 0.05, significantly different from the high-fat diet wild-type mice. AUC, area under the curve.

In vivo metabolic parameters, intramyocellular lipid metabolite profile, and insulin signaling in db/db mice treated with myriocin. RER (A), whole-body oxygen consumption (B), heat production (C), and ambulatory activity (D) in db/+ heterozygous mice, and db/db mice treated with vehicle control or myriocin. Gastrocnemius triacylglycerol (E), long-chain acyl-CoA (F), diacylglycerol (G), and ceramide levels (H) in db/+ heterozygous mice, and db/db mice treated with vehicle control or myriocin. I: Insulin stimulated Akt phosphorylation at serine 473, and (J) GSK3β phosphorylation at serine 9 in gastrocnemius muscle of db/+ heterozygous mice and db/db mice treated with vehicle control or myriocin. Values represent mean ± SE (n = 3–5). Differences were determined using either a one-way or two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from the db/db control mice. †P < 0.05, significantly different from the db/+ heterozygous mice.

Prevention of insulin resistance in db/db mice via myriocin treatment. A: Pretreatment glucose tolerance test (GTT) in db/db mice at 6 weeks of age. B: GTT in db/db mice treated with vehicle control or myriocin. C: Respective areas under the curve for the post-treatment GTT in db/db mice. D: Insulin tolerance test (ITT) in db/db mice treated with vehicle control or myriocin. E: Percent change in blood glucose levels during the ITT. F: Fed and fasted plasma glucose levels in db/db mice treated with vehicle control or myriocin. Values represent mean ± SE (n = 5–6). Differences were determined using either a two-tailed Student t test, or a one-way or two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from the db/db control mice.

Inhibition of SPT1 reduces skeletal muscle ceramide levels with no effect on other lipid metabolites. A–D: Gastrocnemius triacylglycerol (TAG) (A), long-chain acyl-CoA (B), ceramide (C), and diacylglycerol (D) levels in low-fat–fed and obese insulin-resistant mice treated with either vehicle control or myriocin. Values represent mean ± SE (n = 4–8). Differences were determined using a two-way ANOVA followed by Bonferroni post hoc analysis. *P < 0.05, significantly different from the low-fat diet counterpart. †P < 0.05, significantly different from the high-fat diet control mice. E–H: Correlation between the respective areas under the curve during the glucose tolerance test and ceramide (E), TAG (F), long-chain acyl-CoA (G), and diacylglycerol (H) content of (n = 14–18) samples. Correlation was determined via Pearson correlation test. R, multivariate correlation coefficient. AUC, area under the curve.

Inhibition of serine palmitoyl transferase 1 (SPT1) reverses high-fat diet–induced insulin resistance and improves insulin signaling. A: Glucose tolerance test in low-fat–fed and obese insulin-resistant mice treated with either vehicle control or myriocin. B: Area under the curve during the glucose tolerance test. C: Insulin tolerance test in low-fat diet and obese insulin-resistant mice treated with either vehicle control or myriocin. D: Percent change in blood glucose levels during the insulin tolerance test. E: Insulin-stimulated Akt phosphorylation at serine 473, and (F) GSK3β phosphorylation at serine 9 in gastrocnemius muscle of obese insulin-resistant mice treated with either vehicle control or myriocin. Values represent mean ± SE (n = 8–12 for A–D; n = 4 for E and F). Differences were determined using either a two-tailed Student t test or a two-way ANOVA followed by a Bonferroni post hoc analysis. *P < 0.05, significantly different from all other groups. †P < 0.05, significantly different from the high-fat diet control mice.

Myriocin treatment reverses the impairment in whole-body oxygen consumption rates caused by DIO. A–C: Twenty-four hour (A), dark cycle (B), and light cycle (C) whole-body oxygen consumption assessment in low-fat diet and obese insulin-resistant mice treated with either vehicle control or myriocin. D: Gastrocnemius muscle citrate synthase activity in vehicle control and myriocin-treated DIO mice. E: PGC1α expression in low-fat diet and obese insulin-resistant mice treated with either vehicle control or myriocin. F: Citrate synthase activity in vehicle control and myriocin-pretreated C2C12 skeletal muscle myotubes exposed to 1.0 mmol/l palmitate for 16 h. Values represent mean ± SE (n = 5–12). Differences were determined using either a two-tailed Student t test or a two-way ANOVA followed by a Bonferroni post hoc analysis. *P < 0.05, significantly different from the low-fat diet counterpart. †P < 0.05, significantly different from the high-fat diet control mice. AUC, area under the curve.