Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

bioRxiv [Preprint]. 2024 Oct 29:2024.10.25.620374. doi: 10.1101/2024.10.25.620374.

Abstract

Complex genetic and dietary cues contribute to the development of obesity, but how these are integrated on a molecular level is incompletely understood. Here, we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, a membrane-bound O-acyltransferase that enriches diet-derived omega-6 ( n -6) polyunsaturated fatty acids (PUFAs) in the phospholipidome. In high-fat diet-fed mice, lowering membrane n -6 PUFA levels by adipocyte-specific Lpcat3 knockout ( Lpcat3 AKO ) or by dietary lipid manipulation leads to dysfunctional triglyceride (TG) storage, ectopic fat deposition and insulin resistance. Aberrant lipolysis of stored TGs in Lpcat3 AKO adipose tissues instigates a non-canonical adaptive response that engages a futile lipid cycle to increase energy expenditure and limit further body weight gain. Mechanistically, we find that adipocyte LPCAT3 activity promotes TG storage by selectively enriching n -6 arachidonoyl-phosphatidylethanolamine at the ER-lipid droplet interface, which in turn favours the budding of large droplets that exhibit greater resistance to ATGL-dependent hydrolysis. Thus, our study highlights the PPARγ-LPCAT3 pathway as a molecular link between dietary n -6 PUFA intake, adipose expandability and systemic energy balance.

Publication types

  • Preprint