Comparing the Independent Effects of Weight Loss or Exercise Training on Skeletal Muscle Lipid Localization and Insulin Sensitivity in Humans

Localized subcellular muscle lipid accumulation associates with insulin resistance, but independent effects of weight loss or exercise training are unknown. Forty-six men and women with obesity completed 12-week weight loss only, endurance exercise training only without weight loss, or delayed control interventions. Following weight loss, body weight decreased 10% along with a 42% increase in insulin sensitivity. After exercise training, VO2peak increased 9% along with a 23% increase in insulin sensitivity. Whole muscle triacylglycerols (TAGs) increased in the control group, while mitochondrial/endoplasmic reticulum (ER) TAG decreased after weight loss and cytosolic TAGs increased after exercise training. Exercise training increased whole muscle total and 1,2-diacylglycerols (1,2-DAGs) through enhanced cytosolic storage. Total mitochondrial DAGs decreased after weight loss yet increased following exercise training and control. Exercise training increased cytosolic storage of most sphingolipids. Differential gene expression analysis revealed exercise increased mitochondrial function, whereas weight loss reduced inflammation and immune signaling. Only exercise training prevented the inhibition of mitochondrial respiration following exogenous administration of ceramides and di-C18:0-DAG. These data reveal weight loss and exercise training increase cytosolic storage of sphingolipids, weight loss decreases mitochondrial/ER TAG accumulation, and exercise training increases mitochondrial/ER and cytosolic DAGs, suggesting changes in specific subcellular lipid localization may impact muscle insulin sensitization. Skeletal Muscle Diacylglycerol and Sphingolipids – Impact of Localization and Species on Insulin Resistance in Humans, NCT03077360, ClinicalTrials.gov. Article Highlights Subcellular accumulation of lipids is linked to insulin resistance, but changes in localization from weight loss or exercise training have not been thoroughly explored. We evaluated the independent effects of two insulin-sensitizing interventions, weight loss and exercise training, on lipid subcellular distribution in fractionated skeletal muscle, muscle mitochondrial function, and gene expression. Exercise training increased cytosolic storage of diacylglycerols and sphingolipids, and weight loss increased cytosolic sphingosine and decreased mitochondrial/endoplasmic reticulum triacylglycerol and diacylglycerol accumulation. Exercise training prevented the negative effects of mitochondrial lipids on mitochondrial function. Changes in specific subcellular lipid storage help explain muscle insulin sensitization following lifestyle interventions.