The maintenance of glucose homeostasis is vital for survival and overall health. Although blood glucose levels in mammals fluctuate during feeding and fasting, they are typically maintained within a remarkably narrow range of 4–7 mM. This precise balance is achieved through the coordinated actions of multiple tissues. While numerous hormones that stimulate glucose production have been identified, insulin remains the primary hormone that directly inhibits glucose production and lowers blood glucose levels. However, given the prevalence of insulin resistance in diabetic patients, discovering non-insulin-based hypoglycemic hormones has become a critical and challenging research focus.
On January 2, 2025, the team led by Professor Yiguo Wang from the School of Life Sciences at Tsinghua University, in collaboration with Professor Jiqiu Wang from Ruijin Hospital (Shanghai Jiao Tong University School of Medicine) and Professor Yongfeng Song from the Central Hospital affiliated with Shandong First Medical University, published a groundbreaking study in Nature Metabolism titled “A Feeding-Induced Myokine Modulates Glucose Homeostasis.” This research not only identified and named a new muscle-secreted protein, "Feimin" (feeding-induced myokine), but also elucidated its critical role and underlying mechanisms in glucose regulation.
Discovery and Mechanism of Feimin
In their search for a hormone capable of lowering blood sugar after meals, the researchers analyzed protein changes in mouse serum during fasting and refeeding. They identified a previously enigmatic protein, encoded by B230219D22Rik in mice and C5orf24 in humans, as secreted upon refeeding. Further analysis revealed its secretion source and function, leading to its designation as Feimin.
Using muscle-specific Feimin knockout mice, the study demonstrated that the absence of Feimin resulted in significantly elevated postprandial blood glucose levels compared to wild-type mice. Notably, exogenous Feimin administration, in combination with insulin, significantly reduced blood glucose levels and enhanced AKT signaling, a critical pathway in glucose homeostasis. Feimin exhibited a weaker but longer-lasting activation of AKT compared to insulin (Figure 1A), suggesting its potential as a complementary therapeutic avenue for diabetes treatment.
The Feimin-MERTK Signaling Axis
Through receptor siRNA library screening and high-content analysis, the researchers identified the tyrosine kinase receptor Mer (MERTK) as the receptor for Feimin. In mice with MERTK knockout, postprandial hyperglycemia mirrored that observed in Feimin knockout models.
Clinical genetic analyses further revealed that individuals with the MERTK (R466K) mutation exhibited elevated postprandial blood glucose levels. In vitro experiments demonstrated that the R466K mutation reduced Feimin’s receptor binding capacity and weakened AKT activation, providing a mechanistic explanation for hyperglycemia in mutation carriers (Figure 1B).
Implications and Future Directions
The discovery of the Feimin-MERTK signaling axis offers novel insights into postprandial glucose regulation and identifies promising therapeutic targets for metabolic disorders such as diabetes.
Acknowledgments
This study was led by Associate Professor Yiguo Wang (Tsinghua University), Professor Jiqiu Wang (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine), and Professor Yongfeng Song (Shandong First Medical University). Co-first authors include postdoctoral fellow Xiaoliu Shi, Dr. Xiao Hu, and doctoral student Xinlei Fang (Tsinghua University). Key contributors included Dr. Liangjie Jia, Dr. Fangchao Wei, postdoctoral fellow Ying Peng, doctoral student Menghao Liu, Dr. Fengyi Chen, and Dr. Xiaoli Hu from Yiguo Wang’s lab, as well as Assistant Researcher Aibo Gao, Professor Jie Hong, and Professor Guang Ning from Ruijin Hospital, and Assistant Researcher Ke Zhao from Shandong First Medical University. Special thanks are extended to Associate Professor Xiaohui Liu, Professors Haiteng Deng and Ye-Guang Chen (Tsinghua University), Professor Zhenji Gan (Nanjing University), and Professor Junli Liu (Shanghai Jiao Tong University) for their invaluable support and advice.
This research was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Dushi Program and Pillars of the Nation Funding for Life Sciences at Tsinghua University, and the Tsinghua-Peking Joint Center for Life Sciences.
Figure 1: Schematic representation of Feimin's role in regulating glucose homeostasis.
