Alex Neethu Sara, Khan Habibur Rahaman, Ramachandra Subbaraya Gudde, Medhamurthy Rudraiah
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.
J Endocr Soc. 2023 Jun 7;7(8):bvad076. doi: 10.1210/jendso/bvad076. eCollection 2023 Jul 3.
The shift in maternal energy metabolism characteristic of pregnancy is thought to be driven by various hormonal changes, especially of ovarian and placental steroids. Imbalances in circulating estradiol (E) and progesterone (P) levels during this period are often associated with metabolic disturbances leading to the development of gestational diabetes mellitus (GDM). Since abnormalities in the Wnt pathway effector transcription factor 7-like 2 (TCF7L2) are commonly associated with the occurrence of GDM, we hypothesized that the canonical or β-catenin-dependent Wnt signaling pathway mediates the metabolic actions of E and P.
Our study was aimed at elucidating the metabolic function of the steroids E and P, and examining the role of the canonical Wnt signaling pathway in mediating the actions of these steroids.
The ovariectomized (OVX) rat was used as a model system to study the effect of known concentrations of exogenously administered E and P. Niclosamide (Nic) was administered to block Wnt signaling. 3T3-L1 cells were used to analyze changes in differentiation in the presence of the steroids or niclosamide.
In the present study, we observed that E enhanced insulin sensitivity and inhibited lipogenesis while P increased lipogenic gene expression-in 3T3-L1 adipocytes, and in adipose tissue and skeletal muscle of OVX rats when the dosage of E2 and P4 mimicked that of pregnancy. Both E and P were also found to upregulate Wnt signaling. Nic nhibited the steroid-mediated increase in Wnt signaling in adipocytes and OVX rats. The insulin-sensitizing and antilipogenic actions of E were found to be mediated by the canonical Wnt pathway, but the effects of P on lipogenesis appeared to be independent of it. Additionally, it was observed that inhibition of Wnt signaling by Nic hastened adipogenic differentiation, and the inhibitory effect of E on differentiation was prevented by Nic.
The findings presented in this study highlight the role of steroids and Wnt pathway in glucose and lipid metabolism and are relevant to understanding the pathophysiology of metabolic disorders arising from hormonal disturbances.
孕期母体能量代谢的转变被认为是由多种激素变化驱动的，尤其是卵巢和胎盘类固醇激素的变化。在此期间，循环雌二醇（E）和孕酮（P）水平失衡常与代谢紊乱相关，进而导致妊娠期糖尿病（GDM）的发生。由于Wnt信号通路效应转录因子7样2（TCF7L2）异常通常与GDM的发生有关，我们推测经典的或β-连环蛋白依赖的Wnt信号通路介导了E和P的代谢作用。
我们的研究旨在阐明类固醇激素E和P的代谢功能，并研究经典Wnt信号通路在介导这些类固醇激素作用中的作用。
采用去卵巢（OVX）大鼠作为模型系统，研究已知浓度的外源性E和P的作用。给予氯硝柳胺（Nic）以阻断Wnt信号。使用3T3-L1细胞分析类固醇或氯硝柳胺存在时的分化变化。
在本研究中，我们观察到，当E2和P4的剂量模拟孕期水平时，E增强了胰岛素敏感性并抑制脂肪生成，而P增加了脂肪生成基因的表达——在3T3-L1脂肪细胞中，以及在OVX大鼠的脂肪组织和骨骼肌中。还发现E和P均上调Wnt信号。Nic抑制了类固醇介导的脂肪细胞和OVX大鼠中Wnt信号的增加。发现E的胰岛素增敏和抗脂肪生成作用是由经典Wnt通路介导的，但P对脂肪生成的作用似乎与之无关。此外，观察到Nic抑制Wnt信号会加速脂肪生成分化，并且Nic可阻止E对分化的抑制作用。
本研究结果突出了类固醇和Wnt信号通路在葡萄糖和脂质代谢中的作用，有助于理解激素紊乱引起的代谢紊乱的病理生理学。
