• Huang Zhifeng's Research Group of the Academician Li Xiaokun's Team Made Significant Progress in FGF and Diabetes Research

    On December 14th, Professor Huang Zhifeng's research group from the Academician Li Xiaokun's team at WMU published an article, entitled “Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects”, in Nature Communications online (IF: 14.919). The study revealed the role and molecular mechanism of paracrine FGF4 in increasing the glucose uptake in skeletal muscle to resist Type 2 Diabetes (T2D) by upregulating GLUT4 expression and translocation to the cell membrane in skeletal muscle, providing a new candidate drug molecule for the treatment of T2D and related metabolic diseases. 

    Data from the International Diabetes Federation (IDF) shows that around 10% of the world's adults have diabetes, an alarming 537 million people. The prevalence and number of adults with diabetes in China are ranked first in the world, with a sudden increase from 90 million in 2011 to 140 million in 2021, of which more than 90 percent are T2D. The current therapeutic drugs for T2D have different degrees of adverse effects, so it is urgent to explore more new targets and new drugs. 

    Huang Zhifeng's research group has been focusing on the key scientific problems of FGF and metabolic regulation in recent years. In this study, a new member of the FGF family, the paracrine FGF4, was identified by testing multiple cognate paracrine FGFs of FGFR1c. Paracrine FGF4 has similar anti-hyperglycemic effects to FGF1. Further analysis of Fgf4 and FGF1 showed that paracrine FGFs exert their superior glycemic control by targeting skeletal muscle. FGFR1c, which is abundantly expressed on the surface of muscle cells, is the key receptor mediating the anti-hypoglycemic activity of FGF4 / FGF1. FGFR1c activates PLCg after receiving the signal from FGF4 / FGF1. With the help of second messenger IP3, it induces the release of Ca2+ from intracellular stores, activates the CaMKK2-AMPK signaling pathway, promotes the upregulation and translocation of the glucose transporter GLUT4 's to the skeletal muscle cell membrane, thus inducing potent anti-hypoglycemic effects. This new molecular cascade delivery process is completely different from the classical insulin signaling pathway, which provides a scientific explanation for the fact that FGF does not cause hypoglycemic adverse effects of insulin. 

    Based on the above findings, Huang Zhifeng's research group also elucidated the molecular basis for the inferior potency of endocrine FGF21 to FGF4/FGF1 in glucose-lowering activities. The skeletal muscle lacks β-klotho, a co-receptor of endocrine FGF21, so FGF21 can't activate the FGFR1c pathway to regulate glucose metabolism in muscle. Research also found that long-term administration of FGF4 inhibits adipose macrophage infiltration and inflammation, significantly improves insulin resistance, and does not cause adverse effects such as tissue hyperplasia. 

    This study is the first to comprehensively explain the pharmacological mechanism of paracrine FGF in regulating blood glucose and improving insulin resistance, which provides new ideas and strategies for the prevention and treatment of T2D and related metabolic diseases. Its related work was supported by grants from National Key R&D Program of China, Natural Science Foundation of China, Key R&D Program of the Ministry of Science and Technology, and so on. Professor Huang Zhifeng is the corresponding author and last author of the paper. Professor Moosa Mohammadi, Professor Ren Jun from Zhongshan Hospital Affiliated to Fudan University, Professor Li Pingping from Chinese Academy of Medical Sciences and Peking Union Medical College are co-corresponding authors. Ying Lei, a young teacher at WMU, and doctoral candidates Wang Luyao, Guo Kaiwen, Hou Yushu are co-first authors.

    (Translated by Yu Yena and reviewed by Sun You.)