Deis Jessica, Lin Te-Yueh, Bushman Theresa, Chen Xiaoli
Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN 55455, USA.
Cells. 2022 May 3;11(9):1535. doi: 10.3390/cells11091535.
Apart from a well-known role in the innate immune system, lipocalin 2 (Lcn2) has been recently characterized as a critical regulator of thermogenesis and lipid metabolism. However, the physiological mechanism through which Lcn2 regulates cellular metabolism and thermogenesis in adipocytes remains unknown. We found that Lcn2 expression and secretion are significantly upregulated by arachidonic acid (AA) and mTORC1 inhibition in differentiated inguinal adipocytes. AA-induced Lcn2 expression and secretion correlate with the inflammatory NFkB activation. Lcn2 deficiency leads to the upregulation of cyclooxygenase-2 (COX2) expression, as well as increased biosynthesis and secretion of prostaglandins (PGs), particularly PGE2 and PGD2, induced by AA in adipocytes. Furthermore, Lcn2 deficiency affects the mTOR signaling regulation of thermogenic gene expression, lipogenesis, and lipolysis. The loss of Lcn2 dismisses the effect of mTORC1 inhibition by rapamycin on COX2, thermogenesis genes, lipogenesis, and lipolysis, but has no impact on p70 S6Kinase-ULK1 activation in Lcn2-deficient adipocytes. We conclude that Lcn2 converges the COX2-PGE2 and mTOR signaling pathways in the regulation of thermogenesis and lipid metabolism in adipocytes.
除了在先天免疫系统中发挥众所周知的作用外，脂联素2（Lcn2）最近还被确定为产热和脂质代谢的关键调节因子。然而，Lcn2调节脂肪细胞中细胞代谢和产热的生理机制仍不清楚。我们发现，在分化的腹股沟脂肪细胞中，花生四烯酸（AA）和mTORC1抑制可显著上调Lcn2的表达和分泌。AA诱导的Lcn2表达和分泌与炎症性NFkB激活相关。Lcn2缺乏导致脂肪细胞中由AA诱导的环氧合酶-2（COX2）表达上调，以及前列腺素（PGs），特别是PGE2和PGD2的生物合成和分泌增加。此外，Lcn2缺乏影响产热基因表达、脂肪生成和脂肪分解的mTOR信号调节。Lcn2的缺失消除了雷帕霉素对COX2、产热基因、脂肪生成和脂肪分解的mTORC1抑制作用，但对Lcn2缺陷型脂肪细胞中p70 S6激酶-ULK1激活没有影响。我们得出结论，Lcn2在调节脂肪细胞产热和脂质代谢过程中汇聚了COX2-PGE2和mTOR信号通路。
