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The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects.

Muscle biopsies were conducted in lean (L, 22.6 ± 0.5 kg/m², n = 8), Class I (CI, 32.1 ± 0.4 kg/m², n = 7) and Class II&III obese (CII&III, 45.6 ± 1.1 kg/m², n = 15) women for acyl CoA, sphingolipid and DAG profiling. Intramyocellular triglyceride (IMTG) content was determined by histology. FAO was assessed by incubating muscle homogenates with [1‐C]palmitate and measuring CO₂ production. Cardiolipin content was quantified as an index of mitochondrial content. Lipid metabolism proteins, DGAT1, PLIN5, and PNPLA2 were …