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Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity

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posted on 2023-08-28, 15:21 authored by Mulin He, Zhiqiang Li, Victoria Sook Keng Tung, Meixia Pan, Xianlin Han, Oleg Evgrafov, Xian-Cheng Jiang

Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.

Funding

This work was supported by VA Merit 000900-01, NIH HL139582, and NIH RO1HL149730 grants to Xian-Cheng Jiang; and by P30 AG013319 and P30 AG044271 to the Lipidomics Core (Xianlin Han).

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