Signal transduction links intramyocellular triglycerides to muscle insulin resistance in obesity

Abstract

In obesity, both the content and turnover of intramyocellular triglycerides (imcTG) in skeletal muscle are increased and the abnormality is associated with muscle insulin resistance (MIR). Diacylglycerol (DAG) and ceramide (Cer) in myocytes are also elevated; they act on PKC system to impair insulin sensitivity. To test the hypothesis that imcTG increases DAG and Cer fluxes thereby causing MIR, 14C‐triolein and 3H‐phosphatidylcholine were incubated in homogenate of gastrocnemius muscle from lean (n=4) and obese (n=4) rats. Plasma membrane and cytosol were prepared from incubated homogenates, the lipids extracted, DAG and Cer isolated by TLC and their 14C‐radioactivity was used to represent their flux from imcTG. DAG flux to plasma membrane in obese rats was greater (10.1±2.1 vs. 1.6±0.3 nmol/g•min, P<0.01), so was DAG flux to cytosol (55±6.1 vs. 3.9±0.7 nmol/g•min, P<0.01). In contrast, DAG flux to plasma membrane from phospholipids (PL) was lower in obese rats (0.12±0.02 vs. 0.28±0.1 nmol/g•min, P<0.05), consistent with reduced PL content (Horm. Metab. Res. 37:773, 2005). Cer flux to plasma membrane in obese rats was also higher (0.23±0.01 vs. 0.17 0.02 nmol/g•min, P<0.05) whereas the flux from PL was lower (0.02±0.005 vs. 0.06±0.02 g·min, P<0.05). The novel finding indicated that imcTG is a significant and preferred source of DAG and Cer in myocytes of obese rats. Therefore, imcTG contributes to MIR via PKC signaling pathways, explaining the imcTG‐MIR correlation.