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Remodeling glycerophospholipids affects obesity-related insulin signaling in skeletal muscle
Michael J. Wolfgang
Michael J. Wolfgang
Published April 15, 2021
Citation Information: J Clin Invest. 2021;131(8):e148176. https://doi.org/10.1172/JCI148176.
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Commentary Article has an altmetric score of 2

Remodeling glycerophospholipids affects obesity-related insulin signaling in skeletal muscle

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Abstract

It has long been known that fatty acids can either adversely or positively affect insulin signaling in skeletal muscle, depending on chain length or saturation, and can therefore be primary drivers of systemic insulin sensitivity. However, the detailed mechanisms linking fatty acids to insulin signaling in skeletal muscle have been elusive. In this issue of the JCI, Ferrara et al. suggest a model whereby membrane lipid remodeling mediates skeletal muscle insulin sensitivity. The authors demonstrate that membrane glycerophospholipid fatty acid remodeling by lysophosphatidylcholine acyltransferase 3 (LPCAT3) in skeletal muscle from subjects with obesity was induced, suppressing insulin signaling and glucose tolerance. Loss or gain of LPCAT3 function in mouse models showed that Lpcat3 was both required and sufficient for high-fat diet–induced muscle insulin resistance. These results suggest that the physiochemical properties of muscle cell membranes may drive insulin sensitivity and, therefore, systemic glucose intolerance.

Authors

Michael J. Wolfgang

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Figure 1

Model of diet-induced lipid bilayer changes in skeletal muscle that result in insulin resistance.

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Model of diet-induced lipid bilayer changes in skeletal muscle that resu...
When incorporating lipids into the plasma membrane, LPCAT3, an enzyme involved with phospholipid transacylation, esterifies a fatty acid onto a lysophospholipid from an acyl-CoA donor. Ferrara et al. (7) showed that an imbalance of glycerophospholipid remodeling in skeletal muscle occurs with obesity. In people, skeletal muscle remodeling was associated with an increase in LPCAT3. Loss or gain of Lpcat3 in mouse models showed that Lpcat3 is required and sufficient for inducing muscle insulin resistance following a high-fat diet. Muscle cell membrane composition may drive insulin sensitivity and glucose intolerance by influencing oxidation and plasma membrane rigidity. LPCAT3-dependent changes in plasma membrane may increase susceptibility to lipid oxidation by increasing the quantity of oxidation-sensitive fatty acids. Moreover, membrane fluidity may directly affect insulin signaling efficacy by changing accessibility to insulin receptors or altering glucose transporter trafficking.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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