Riecan Martin, Domanska Veronika, Lupu Cristina, Patel Maulin, Vondrackova Michaela, Rossmeisl Martin, Saghatelian Alan, Lupu Florea, Kuda Ondrej
Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czechia.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
bioRxiv. 2023 Nov 16:2023.11.15.567158. doi: 10.1101/2023.11.15.567158.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.
羟基脂肪酸的脂肪酸酯（FAHFAs）是具有抗炎和抗糖尿病特性的内源性生物活性脂质。尽管它们具有治疗潜力，但关于FAHFA代谢的性别特异性差异却知之甚少。本研究调查了一种FAHFA水解酶——雄激素依赖性组织因子途径抑制物调节蛋白（ADTRP）的作用。此外，利用代谢组学和脂质组学评估了FAHFA水平的组织特异性差异，重点关注性腺周围白色脂肪组织（pgWAT）、皮下白色脂肪组织（scWAT）、棕色脂肪组织（BAT）、血浆和肝脏。我们发现，与雄性小鼠相比，雌性小鼠的pgWAT、scWAT和BAT中的FAHFA水平更高。FAHFA水平与mRNA呈负相关，在pgWAT和scWAT中，雌性的mRNA表达明显低于雄性。然而，在血浆和肝脏FAHFA水平上未观察到性别之间的显著差异。ADTRP缺失对两性pgWAT的代谢组和脂质组影响最小。然而，我们发现雌性小鼠的pgWAT中含有FAHFAs（一种FAHFA代谢储存库）的三酰甘油雌内酯的内源性水平更高。这些发现表明，FAHFA水平的性别依赖性差异主要发生在特定的白色脂肪组织库中，并可能调节脂肪细胞中的局部胰岛素敏感性。然而，需要进一步研究以充分理解性别对人类FAHFA代谢影响的潜在机制和意义。
