Feimin

Maintaining blood glucose homeostasis during fasting and feeding is crucial for the prevention of dysregulation that can lead to either hypo- or hyperglycaemia. Here we identified feimin, encoded by a gene with a previously unknown function (B230219D22Rik in mice, C5orf24 in humans), as a key modulator of glucose homeostasis. Feimin is secreted from skeletal muscle during feeding and binds to its receptor, receptor protein tyrosine kinase Mer (MERTK), promoting glucose uptake and inhibiting glucose production by activation of AKT. Administration of feimin and insulin synergistically improves blood glucose homeostasis in both normal and diabetic mice. Notably, a specific single nucleotide polymorphism (rs7604639, G>A) within the MERTK gene, causing an amino acid substitution (R466K) within the feimin-MERTK binding region, leads to reduced association with feimin and elevated postprandial blood glucose and insulin levels in humans. Our findings underscore a role of the feimin-MERTK signalling axis in glucose homeostasis, providing valuable insights into potential therapeutic avenues for diabetes.

Lipid droplet accumulation in microglia, microglia‐mediated neuroinflammation, and subsequent neuronal damage are hallmark features of high‐fat diet (HFD)‐induced cognitive impairment. In this analysis, this is proposed that a new molecule feimin (B230219D22Rik in mice) is a key negative regulator of LD accumulation and the inflammatory response in HFD‐induced cognitive impairment. To test this hypothesis, BV2 microglia is exposed to palmitic acid (PA) in vitro, mimicking the effects of an HFD. This is found that feimin expression is significantly increased following high‐lipid stimulation. Feimin‐specific knockdown in BV2 cells led to enhanced LD accumulation, exacerbated inflammatory responses and neuronal apoptosis, whereas feimin overexpression has the opposite effect. Mechanistically, immunoprecipitation (IP) assays revealed that an interaction between feimin and AKT suppressed the AKT–mTOR signaling pathway. To further investigate the role of feimin in vivo, microglial feimin‐conditional knockout mice (feiminMic‐/−) is developed. In the HFD model, feiminMic‐/− mice exhibited increased LD accumulation in hippocampal microglia, enhanced inflammation, and neuronal apoptosis, resulting in significant cognitive decline. In conclusion, this findings identified feimin as a key negative regulator of HFD‐induced LD accumulation and the microglia‐mediated inflammation response, suggesting that it is an attractive therapeutic target for cognitive decline associated with HFDs.