Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, China.
Department of Dermatology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Front Endocrinol (Lausanne). 2021 Oct 18;12:668193. doi: 10.3389/fendo.2021.668193. eCollection 2021.
This study aims to investigate whether hypoxia-inducible factor 1α (HIF1α) in the neurons of the mediobasal hypothalamus is involved in the regulation of body weight, glucose, and lipid metabolism in mice and to explore the underlying molecular mechanisms.
HIF1α mice were used. The adeno-associated virus that contained either cre, GFP and syn, or GFP and syn (controls) was injected into the mediobasal hypothalamus to selectively knock out HIF1α in the neurons of the mediobasal hypothalamus. The body weight and food intake were weighed daily. The levels of blood glucose, insulin, total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)were tested. Intraperitoneal glucose tolerance test (IPGTT) was performed. The insulin-stimulated Akt phosphorylation in the liver, epididymal fat, and skeletal muscle were examined. Also, the mRNA expression levels of HIF1α, proopiomelanocortin (POMC), neuropeptide Y (NPY), and glucose transporter protein 4 (Glut4) in the hypothalamus were checked.
After selectively knocking out HIF1α in the neurons of the mediobasal hypothalamus (HIF1αKOMBH), the body weights and food intake of mice increased significantly compared with the control mice ( < 0.001 at 4 weeks). Compared with that of the control group, the insulin level of HIF1αKOMBH mice was 3.5 times higher ( < 0.01). The results of the IPGTT showed that the blood glucose level of the HIF1αKOMBH group at 20-120 min was significantly higher than that of the control group ( < 0.05). The serum TC, FFA, HDL, and LDL content of the HIF1αKOMBH group was significantly higher than those of the control group ( < 0.05). Western blot results showed that compared with those in the control group, insulin-induced AKT phosphorylation levels in liver, epididymal fat, and skeletal muscle in the HIF1αKOMBH group were not as significantly elevated as in the control group. Reverse transcription-polymerase chain reaction (RT-PCR) results in the whole hypothalamus showed a significant decrease in Glut4 mRNA expression. And the mRNA expression levels of HIF1α, POMC, and NPY of the HIF1αKOMBH group decreased significantly in ventral hypothalamus.
The hypothalamic neuronal HIF1α plays an important role in the regulation of body weight balance in mice under normoxic condition. In the absence of hypothalamic neuronal HIF1α, the mice gained weight with increased appetite, accompanied with abnormal glucose and lipid metabolism. POMC and Glut4 may be responsible for this effect of HIF1α.
本研究旨在探讨中脑基底部神经元中的缺氧诱导因子 1α（HIF1α）是否参与调节小鼠的体重、葡萄糖和脂质代谢，并探讨其潜在的分子机制。
使用 HIF1α 基因敲除小鼠。将含有 cre、GFP 和 syn 或 GFP 和 syn（对照）的腺相关病毒注入中脑基底部，以选择性敲除中脑基底部神经元中的 HIF1α。每天称量体重和食物摄入量。检测血糖、胰岛素、总胆固醇（TC）、甘油三酯（TG）、游离脂肪酸（FFA）、高密度脂蛋白（HDL）和低密度脂蛋白（LDL）水平。进行腹腔内葡萄糖耐量试验（IPGTT）。检测肝脏、附睾脂肪和骨骼肌中胰岛素刺激的 Akt 磷酸化水平。此外，还检测了下丘脑 HIF1α、前阿黑皮素原（POMC）、神经肽 Y（NPY）和葡萄糖转运蛋白 4（Glut4）的 mRNA 表达水平。
中脑基底部神经元 HIF1α 选择性敲除后（HIF1αKOMBH），与对照组相比，小鼠体重和食物摄入量明显增加（4 周时 < 0.001）。与对照组相比，HIF1αKOMBH 组的胰岛素水平高 3.5 倍（<0.01）。IPGTT 结果显示，HIF1αKOMBH 组 20-120 分钟时血糖水平明显高于对照组（<0.05）。HIF1αKOMBH 组血清 TC、FFA、HDL 和 LDL 含量明显高于对照组（<0.05）。Western blot 结果显示，与对照组相比，HIF1αKOMBH 组胰岛素诱导的肝脏、附睾脂肪和骨骼肌中 AKT 磷酸化水平升高不明显。全下丘脑逆转录-聚合酶链反应（RT-PCR）结果显示，Glut4mRNA 表达水平显著降低。HIF1αKOMBH 组下丘脑腹侧 HIF1α、POMC 和 NPY 的 mRNA 表达水平显著降低。
在正常氧条件下，下丘脑神经元 HIF1α 在调节小鼠体重平衡中起重要作用。在缺乏下丘脑神经元 HIF1α 的情况下，小鼠食欲增加，体重增加，伴有葡萄糖和脂质代谢异常。POMC 和 Glut4 可能是 HIF1α 产生这种作用的原因。
