美国波士顿儿童医院Rongya Tao研究组宣布他们提出了肝脏胰岛素信号对糖脂代谢的空间调节。该研究于2025年4月16日发表于国际一流学术期刊《细胞—代谢》杂志上。

研究小组让CreER小鼠选择性地破坏门静脉周围（PP）和中心周围（PC）肝细胞的胰岛素信号。PP-胰岛素抵抗已被认为是2型糖尿病患者合并高血糖和过量脂肪生成的驱动因素。

然而，小鼠的PP-胰岛素抵抗损害了脂肪生成并抑制了高脂肪饮食（HFD）诱导的肝成骨病，尽管糖异生和胰岛素升高。相反，PC-胰岛素抵抗减少了HFD诱导的PC脂肪变性，同时保持了正常的葡萄糖稳态，部分原因是糖酵解代谢从肝脏转移到细胞。这些结果证明了胰岛素在PP和PC肝细胞中的不同作用，并提示PC-胰岛素抵抗可能在不损害葡萄糖稳态的情况下治疗肝纤维化。

据了解，肝脏胰岛素敏感性对全身葡萄糖和脂质稳态至关重要。肝脏在空间上被组织成不同的区域，其中肝细胞表达不同的代谢酶；然而，这种分带对胰岛素抵抗引起的代谢失调的功能意义尚不确定。

附：英文原文

Title: Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling

Author: Baiyu He, Kyle D. Copps, Oliver Sthr, Beikl Liu, Songhua Hu, Shakchhi Joshi, Marcia C. Haigis, Morris F. White, Hao Zhu, Rongya Tao

Issue&Volume: 2025-04-16

Abstract: Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.

DOI: 10.1016/j.cmet.2025.03.015

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00207-4