Institute for Diabetes and Cancer (IDC), Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.
Life Sci Alliance. 2021 Feb 3;4(4). doi: 10.26508/lsa.202000898. Print 2021 Apr.
Members of the lipocalin protein family serve as biomarkers for kidney disease and acute phase inflammatory reactions, and are under preclinical development for the diagnosis and therapy of allergies. However, none of the lipocalin family members has made the step into clinical development, mostly due to their complex biological activity and the lack of in-depth mechanistic knowledge. Here, we show that the hepatokine lipocalin 13 (LCN13) triggers glucose-dependent insulin secretion and cell proliferation of primary mouse islets. However, inhibition of endogenous LCN13 expression in lean mice did not alter glucose and lipid homeostasis. Enhanced hepatic secretion of LCN13 in either diet-induced or genetic obesity led to no discernible impact on systemic glucose and lipid metabolism, neither in preventive nor therapeutic setting. Of note, loss or forced LCN13 hepatic secretion did not trigger any compensatory regulation of related lipocalin family members. Together, these data are in stark contrast to the suggested gluco-regulatory and therapeutic role of LCN13 in obesity, and imply complex regulatory steps in LCN13 biology at the organismic level mitigating its principal insulinotropic effects.
脂质运载蛋白家族成员可作为肾脏疾病和急性炎症反应的生物标志物，并且处于过敏诊断和治疗的临床前开发阶段。然而，脂质运载蛋白家族的成员都没有进入临床开发阶段，主要是因为它们具有复杂的生物学活性，而且对其机制的了解还不够深入。在这里，我们发现了肝源脂质运载蛋白 13（LCN13）可触发原代小鼠胰岛的葡萄糖依赖性胰岛素分泌和细胞增殖。然而，在瘦鼠中抑制内源性 LCN13 的表达并没有改变葡萄糖和脂质的稳态。无论是在饮食诱导的肥胖还是遗传肥胖的情况下，增强 LCN13 在肝脏中的分泌，在预防或治疗环境中都不会对全身葡萄糖和脂质代谢产生明显影响。值得注意的是，LCN13 的缺失或强制肝脏分泌并没有引发相关脂质运载蛋白家族成员的任何代偿性调节。总之，这些数据与 LCN13 在肥胖症中的调节血糖和治疗作用形成鲜明对比，表明 LCN13 生物学在机体水平上存在复杂的调节步骤，减轻了其主要的胰岛素增敏作用。
