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 6

LPCAT3-MKO mice are protected from diet-induced skeletal muscle insulin resistance.

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LPCAT3-MKO mice are protected from diet-induced skeletal muscle insulin ...
(A) Intraperitoneal glucose tolerance test (Ctrl n = 6, MKO n = 8). (B) Serum insulin at the 30-minute time point of the glucose tolerance test (Ctrl n = 3, MKO n = 8). (C–F) Hyperinsulinemic-euglycemic clamps were performed in conscious unrestrained mice (Ctrl n = 6, MKO n = 7). (C) Glucose infusion rate required to maintain constant blood glucose of 150 mg/dL during clamp phase. (D) Hepatic glucose output during the clamp phase. (E) Rate of whole-body glucose disposal during the clamp phase. (F) 14C-2-deoxyglucose uptake quantification in soleus and diaphragm muscles during the clamped state. (G–I) Soleus muscles were dissected and incubated with or without 200 μU/mL of insulin. (G) Ex vivo 2-deoxyglucose uptake (n = 5). (H and I) Ser473 phosphorylation and total Akt (n = 5). All data are from HFD-fed mice. Two-way ANOVA with Šidák’s multiple-comparison test (A, F, G, and I) or 2-tailed t tests (B–E) were performed. All data are represented as mean ± SEM. *P ≤ 0.05.