Endothelial-derived FABP4 constitutes the majority of basal circulating hormone and regulates lipolysis-driven insulin secretion.
Endothelial-derived FABP4 constitutes the majority of basal circulating hormone and regulates lipolysis-driven insulin secretion.
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DOI：
10.1172/jci.insight.164642
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发表时间：
2023-07-24
期刊：
影响因子：
8
通讯作者：
Hotamisligil, Gokhan S.
中科院分区：
文献类型：
--
作者：
Inouye, Karen E.;Prentice, Kacey J.;Lee, Alexandra;Wang, Zeqiu B.;Dominguez-Gonzalez, Carla;Chen, Mu Xian;Riveros, Jillian K.;Burak, M. Furkan;Lee, Grace Y.;Hotamisligil, Gokhan S.
脂肪酸结合蛋白4（FABP 4）是脂肪细胞在刺激脂解时分泌的脂质伴侣。在实验模型和人类中，循环FABP 4水平与肥胖和代谢病理密切相关。虽然脂肪细胞被认为是激素FABP 4的主要来源，但这个问题尚未在体内得到明确解决。我们在已知表达该基因的细胞-脂肪细胞（Adipo-KO）、内皮细胞（Endo-KO）、骨髓细胞（Myeloid-KO）和全身（Total-KO）中产生了Fabp 4缺失的小鼠，以检查这些细胞类型对基础和刺激的血浆FABP 4水平的贡献。出乎意料的是，基线血浆FABP 4在Adipo-KO小鼠中没有显著降低，而Endo-KO小鼠相对于WT对照显示约87%的降低。相比之下，Adipo-KO小鼠表现出对脂肪分解的FABP 4应答的诱导降低约62%，而Endo-KO小鼠仅表现出轻度诱导降低，表明脂肪细胞是脂肪分解期间FABP 4增加的主要来源。我们没有检测到任何骨髓对循环FABP 4的贡献。令人惊讶的是，尽管FABP 4的诱导几乎完整，但Endo-KO小鼠显示出与Total-KO小鼠相同的脂肪分解诱导的胰岛素分泌减弱。我们的结论是，内皮细胞是基线激素FABP 4的主要来源，是胰岛素对脂解反应所必需的。
Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with obesity and metabolic pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with Fabp4 deletion in cells known to express the gene — adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) — to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was not significantly reduced in Adipo-KO mice, whereas Endo-KO mice showed ~87% reduction versus WT controls. In contrast, Adipo-KO mice exhibited ~62% decreased induction of FABP4 responses to lipolysis, while Endo-KO mice showed only mildly decreased induction, indicating that adipocytes are the main source of increases in FABP4 during lipolysis. We did not detect any myeloid contribution to circulating FABP4. Surprisingly, despite the nearly intact induction of FABP4, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis.
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影响因子：
17.1
作者：
Burak, M. Furkan;Inouye, Karen E.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
4.3
作者：
Johnson, James D.;Alejandro, Emilyn U.
通讯作者：
Alejandro, Emilyn U.
影响因子：
29
作者：
Eguchi J;Wang X;Yu S;Kershaw EE;Chiu PC;Dushay J;Estall JL;Klein U;Maratos-Flier E;Rosen ED
通讯作者：
Rosen ED
影响因子：
2.7
作者：
Kisanuki, YY;Hammer, RE;Yanagisawa, M
通讯作者：
Yanagisawa, M