Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle
Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai
Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai
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Research Article Metabolism Muscle biology

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Abstract

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle–specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle–specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Authors

Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai

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Figure 5

Whole-body phenotyping of LPCAT3-MKO mice.

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Whole-body phenotyping of LPCAT3-MKO mice. (A) Mice with tamoxifen-induc...
(A) Mice with tamoxifen-inducible skeletal muscle–specific Cre recombinase (HSA-MerCreMer+/–) were crossed with mice with loxP sites flanking exon 3 of the Lpcat3 gene (LPCAT3cKO+/+) to generate skeletal muscle–specific inducible knockout of LPCAT3 (LPCAT3cKO+/+; HSA-MerCreMer+/–) (LPCAT3-MKO). Littermates (LPCAT3cKO+/+; HSA-MerCreMer–/–) (Ctrl) were used as control mice for all experiments. (B) LPCAT3 mRNA in tibialis anterior (Muscle), heart, liver, small intestine, and inguinal white adipose tissue (WAT) (muscle: Ctrl n = 12, MKO n = 15; heart: Ctrl n = 5, MKO n = 6; liver: Ctrl n = 7, MKO n = 8; small intestine: Ctrl n = 4, MKO n = 7; WAT: Ctrl n = 3, MKO n = 7). (C) mRNA of all LPCAT isoforms in tibialis anterior muscles of Ctrl and LPCAT3-MKO mice (Ctrl n = 9, MKO n = 14). (D) Body mass during HFD feeding in Ctrl and LPCAT3-MKO mice (Ctrl n = 8, MKO n = 11). (E) Epididymal WAT mass (Ctrl n = 6, MKO n = 9). (F–I) Ctrl and LPCAT3-MKO mice were placed in metabolic chambers for measurement of food consumption (F), VO2 (G), activity (H), and respiratory exchange ratio (RER) (I) (Ctrl n = 6, MKO n = 10). (J) Fasting glucose (Ctrl n = 5, MKO n = 9). (K) Fasting insulin (Ctrl n = 6, MKO n = 9). All data except those in A are from HFD-fed mice. Two-tailed t tests (B, C, E, F, J, and K) or 2-way ANOVA with Šidák’s multiple-comparison test (D and G–I) was performed. All data are represented as mean ± SEM. *P ≤ 0.05.