Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function

Abstract

Skeletal muscle insulin resistance is an early defect in the development of type 2 diabetes. Lipid overload induces insulin resistance in muscle and alters the composition of the sarcoplasmic reticulum (SR). To test the hypothesis that skeletal muscle phospholipid metabolism regulates systemic glucose metabolism, we perturbed choline/ethanolamine phosphotransferase 1 (CEPT1), the terminal enzyme in the Kennedy pathway of phospholipid synthesis. In C2C12 cells, CEPT1 knockdown altered SR phospholipid composition and calcium flux. In mice, diet-induced obesity, which decreases insulin sensitivity, increased muscle CEPT1 expression. In high-fat diet–fed mice with skeletal muscle–specific knockout of CEPT1, systemic and muscle-based approaches demonstrated increased muscle insulin sensitivity. In CEPT1-deficient muscles, an altered SR phospholipid milieu decreased sarco/endoplasmic reticulum Ca2+ ATPase–dependent calcium uptake, activating calcium-signaling pathways known to improve insulin sensitivity. Altered muscle SR calcium handling also rendered these mice exercise intolerant. In obese humans, surgery-induced weight loss increased insulin sensitivity and decreased skeletal muscle CEPT1 protein. In obese humans spanning a spectrum of metabolic health, muscle CEPT1 mRNA was inversely correlated with insulin sensitivity. These results suggest that high-fat feeding and obesity induce CEPT1, which remodels the SR to preserve contractile function at the expense of insulin sensitivity.

Muscle‐specific Perilipin2 down‐regulation affects lipid metabolism and induces myofiber hypertrophy

“…Finally, also phospholipids may contribute to the muscle phenotype because PE has been reported to affect skeletal muscle growth and PC:PE ratio is inversely correlated to insulin sensitivity . Recent studies in mice showed an impaired calcium uptake and muscle weakness when PE is reduced and consequently, the PC:PE ratio is increased . Interestingly, we found that Plin2 down‐regulation, but not Plin2 overexpression, decreased PC:PE ratio due to a strong increase in PE.…”

“…21,56,57 Recent studies in mice showed an impaired calcium uptake and muscle weakness when PE is reduced and consequently, the PC:PE ratio is increased. 58,59 Interestingly, we found that Plin2 down-regulation, but not Plin2 overexpression, decreased PC:PE ratio due to a strong increase in PE. This phospholipid change may also contribute to the growth-promoting action of Plin2 down-regulation.…”

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

“…A clinical study conducted in lean control and overweight but non‐diabetic patients showed that baseline fasting plasma insulin and HOMA‐IR were positively correlated with erythrocyte membrane phosphatidylethanolamine and phosphatidylcholine content in the whole population . Another clinical study in obese patients, who underwent surgery‐induced weight loss, demonstrated that the mRNA level of choline/ethanolamine phosphotransferase 1 (a key protein in final step of phosphatidylcholine synthesis) was inversely correlated with insulin sensitivity . The ratio of phosphatidylcholine to phosphatidylethanolamine has also attracted much attention.…”

“…In a mouse model, reduced phosphatidylcholine levels mediated by hepatic specific knockout of CT, which is the key enzyme for phosphatidylcholine biosynthesis, were shown to lead to triacylglycerol accumulation but had no effect on insulin sensitivity . However, perturbed phosphatidylcholine synthesis through skeletal muscle specific knockdown of CEPT, the rate‐limiting enzyme in the major route for phosphatidylcholine production, resulted in improved insulin sensitivity in mice treated with a high‐fat diet . This influence on insulin sensitivity was thought to be related to an increase in activation of calcium‐signalling pathways via decreased sarco/ER Ca 2+ ATPase‐dependent calcium uptake (Figure ).…”

Looking Beyond Structure: Membrane Phospholipids of Skeletal Muscle Mitochondria

“…In mice with skeletal muscle-specific knockout of ET, reduction in cellular PE coincided with increased skeletal muscle mitochondrial biogenesis and exercise endurance [35]. In contrast, muscle-specific deletion of CEPT1 had no apparent effect on skeletal muscle mitochondria but promoted muscle weakness [36]. Differences in mitochondrial phenotype promoted by deletion of PSD, ET, or CEPT1 demonstrate the complexity of skeletal muscle phospholipid metabolism.…”