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A feeding-induced myokine modulates glucose homeostasis

Nature Metabolism (2025)Cite this article

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Abstract

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.

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Fig. 1: Feimin regulates glucose homeostasis.
Fig. 2: Feimin and insulin synergistically improve blood glucose levels in diabetic mice.
Fig. 3: MERTK is a receptor of feimin.
Fig. 4: Feimin modulates glucose metabolism via MERTK.
Fig. 5: MERTK impacts glucose homeostasis in humans.

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Data availability

The mass spectrometry proteomics data have been deposited in the ProteomeXchange database via the PRIDE partner repository, with dataset identifiers PXD028153 and PXD039889. All additional data supporting the findings of this study, including experimental analysis data and statistical information related to immunoblot images, are available in the Supplementary Information. A reporting summary for this article is also available as Supplementary Information. Source Data are provided with this paper.

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Acknowledgements

We thank X. Liu, H. Deng, Z. Gan, J. Liu, Y.-G. Chen and all laboratory members for discussion and technical help. We thank I. Hanson for editing. We thank the Core Facility for Biomolecule Preparation and Characterization at Technology Center for Protein Science, Tsinghua University for assistance. This work was supported by grants from the Ministry of Science and Technology of the People’s Republic of China (number 2021YFA0804801), the National Natural Science Foundation of China (numbers 82088102, 31830040 and 91957206), Dushi Program and Pillars of the Nation Funding for Life Sciences, Tsinghua university (to Y.W.).

Author information

Author notes

  1. These authors contributed equally: Xiaoliu Shi, Xiao Hu, Xinlei Fang.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Xiaoliu Shi, Xiao Hu, Xinlei Fang, Liangjie Jia, Fangchao Wei, Ying Peng, Menghao Liu, Fengyi Chen, Xiaoli Hu & Yiguo Wang

  2. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Aibo Gao, Jie Hong, Guang Ning & Jiqiu Wang

  3. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai, China

    Aibo Gao, Jie Hong, Guang Ning & Jiqiu Wang

  4. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China

    Ke Zhao & Yongfeng Song

  5. Shandong Institute of Endocrine & Metabolic Disease, Jinan, China

    Ke Zhao & Yongfeng Song

  6. Central Hospital Affiliated to Shandong First Medical University, Jinan, China

    Ke Zhao & Yongfeng Song

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  1. Xiaoliu Shi
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Contributions

X.S., Xiao Hu, X.F., L.J., F.W., Y.P., M.L., F.C. and Xiaoli Hu conducted the experiments. A.G., J.H., G.N. and J.W. analysed MERTK SNPs. K.Z. and Y.S. collected human blood samples for measurement of plasma feimin. Y.W. conceived, designed and supervised the study. Y.W., X.S. and Xiao Hu wrote the paper. All authors reviewed and commented on the paper.

Corresponding authors

Correspondence to Yongfeng Song, Jiqiu Wang or Yiguo Wang.

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Competing interests

Y.W., X.S. and Xiao Hu have one pending patent application. The other authors declare no competing interests.

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Nature Metabolism thanks C. R. Kahn and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: R. Dewal, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Characterization of feimin.

a, Left panel, silver-stained SDS-polyacrylamide gel showing the profile of plasma proteins from 8-10-week-old male mice after overnight fasting (Fasted) or overnight fasting followed by refeeding (Refed). In the refed group, samples were collected 1 hr after the start of feeding. Mouse plasma proteins were obtained using the ProteoMiner Protein Enrichment Kit. Right panel, peptide sequence of feimin (B230219D22Rik) identified by mass spectrometry. b, The MS/MS spectra of the identified peptides from feimin are shown. The labelled peaks show the masses of y or b ions of the peptide. c, Alignment of the amino acid sequence of feimin from different species. d, Immunostaining showing the localization of feimin-3×Flag in HEK293T cells. Scale bar, 10 µm. e, Immunoblots showing the expression and secretion of feimin-3×Flag in HEK293T cells after 48-hr transfection. TCL, total cell lysate. f, Schematic showing the purification of feimin-3×Flag from Hi-5 culture medium and the subsequent identification of the feimin sequence by LC-MS/MS (left panel). The identified amino acids are marked in red (right panel). g, Effect of overnight fasting and refeeding on blood glucose levels. n = 5 male mice for each indicated time. h, Effect of overnight fasting (Fasted) and refeeding on plasma feimin, insulin, and blood glucose levels in female mice. n = 5 female mice for each time point. i, Effect of intraperitoneal administration of glucose (1 g·kg−1) on plasma blood glucose levels. n = 7 male mice for each indicated time. Data are shown as mean ± s.e.m.

Source data

Extended Data Fig. 2 Feimin is a feeding-induced myokine.

a, qPCR results showing relative mRNA levels of feimin in different mouse tissues. Gastro, gastrocnemius muscle; eWAT, epidydimal white adipose tissue; BAT, brown adipose tissue. n = 5 mice. b, Immunoblots showing the levels of feimin protein in different tissues from 8-10-week-old male mice. cFeimin, cellular feimin. c, qPCR results showing relative mRNA levels of feimin in different human tissues. n = 3 humans. d, Top panel, generation of feimin−/− mice by CRISPR-Cas9. A deletion of 97 bp was introduced into exon 2 of the feimin gene. Bottom panel, the partial N-terminal sequence of WT feimin and the full sequence of the truncated feimin protein product in feimin−/− mice are shown. The frame-shifted amino acids of feimin generated by the deletion in feimin−/− mice are shown in red. e, Immunoblots showing global knockout of feimin. cFeimin, cellular feimin. f, Generation of feimin intestine-specific knockout (IKO), muscle-specific knockout (MKO), liver-specific knockout (LKO) and adipose tissue knockout (FKO) mice (left panel) and immunoblots showing tissue-specific knockout of feimin (right panel). cFeimin, cellular feimin; Intes, intestine. g, Plasma feimin levels from WT (fl/fl) and muscle-specific feimin knockout (MKO) mice. Samples were collected after overnight fasting (Fasted) and then 30 min after glucose injection (1 g kg−1, Fasted/Glc). 8-10-week-old male mice were used in this assay. n = 8 mice. h, Plasma feimin levels from WT (fl/fl) and muscle-specific feimin knockout (MKO) mice. Samples were collected after 6 hr fasting and then 30 min after insulin injection (1 U kg−1). 8-10-week-old male mice were used in this assay. n = 8 mice. Data are shown as mean ± s.e.m. Statistical comparisons were performed using two-way ANOVA followed by Tukey’s test (g, h). All individual points and P values are shown.

Source data

Extended Data Fig. 3 Feimin is secreted in myofibers and myotubes.

a, Effect of serum on medium feimin levels in cultured myofibers of extensor digitorum longus (EDL) muscle from WT mice or feimin MKO mice. The myofibers were treated for 1 hr with 10% serum from feimin−/− mice (feimin global knockout) after overnight fasting (fasted serum) or 1 hr refeeding (refed serum). n = 6 biological replicates. b, Effect of different glucose (Glc) doses on medium feimin levels in cultured myofibers of EDL muscle from WT mice or feimin MKO mice. The myofibers were treated in the presence or absence of glucose for 1 hr. n = 6 biological replicates. c, Effect of glucose (Glc, 10 mM) and/or insulin (INS, 100 nM) on medium feimin levels in cultured myofibers of EDL muscle from WT mice or feimin MKO mice. The myofibers were treated in the presence or absence of glucose and/or insulin for 1 hr. n = 6 biological replicates. d, Effect of serum on medium feimin levels in cultured myotubes from WT mice or feimin−/− mice (feimin global knockout). The mature myotubes were treated for 1 hr with 10% serum from feimin−/− mice after overnight fasting (fasted serum) or 1 hr refeeding (refed serum). n = 6 biological replicates. e, Effect of different glucose (Glc) doses on medium feimin levels in cultured myotubes from WT mice or feimin−/− mice. The mature myotubes were treated in the presence or absence of glucose for 1 hr. n = 6 biological replicates. f, Effect of glucose (Glc, 10 mM) and/or insulin (INS, 100 nM) on medium feimin levels in cultured myotubes from WT mice or feimin−/− mice. The mature myotubes were treated in the presence or absence of glucose and/or insulin for 1 hr. n = 6 biological replicates. g, Effect of glucose (Glc, 10 mM) and/or insulin (INS, 100 nM) on feimin mRNA in cultured myotubes from WT mice or feimin−/− mice. The mature myotubes were treated in the presence or absence of glucose and/or insulin for 1 hr. n = 3 biological replicates. h, Effect of secretion inhibitors on medium feimin levels in cultured myotubes. Mature myotubes were pretreated with or without Brefeldin A (5 µg ml−1), Glibenclamide (50 µM), GW4869 (10 µM), or Manumycin A (10 µM) for 30 min, followed by treatment with glucose (10 mM) and insulin (100 nM) for 1 hr. n = 6 biological replicates. i, Immunoblots showing that feimin is associated with exosomes. Purified exosomes from myotubes were digested with (PK + ) or without (PK-) Proteinase K. CD81 is a transmembrane marker protein of exosomes, and TSG101 is a lumenal marker protein of exosomes. TCL, total cell lysate. j, Effect of mTOR inhibitor (Torin 1, 250 nM), AMPK activator (A-769662, 10 µM), or AMPK inhibitor (Compound C, 10 µM) on medium feimin levels. Matured myotubes were pretreated with or without these chemicals for 30 min, followed by treatment with glucose (10 mM) and insulin (100 nM) for 1 hr. n = 6 biological replicates. k, Model showing the effect of glucose and insulin on feimin secretion. When glucose and insulin levels are high, mTOR activity is stimulated while the activity of AMPK, which has an inhibitory role in feimin secretion, is dampened. When glucose and insulin levels are low, mTOR is downregulated and AMPK is activated, thus reducing feimin secretion. Data are shown as mean ± s.e.m. Statistical comparisons were performed using two-way ANOVA followed by Tukey’s test (a-h, j). All individual points and P values are shown.

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Extended Data Fig. 4 Effect of feimin muscle-specific knockout on metabolism.

a-m, Effect of feimin MKO on body weight (a), food intake (b), water intake (c), fat mass ratio (d), movement (e), energy expenditure (f), respiratory exchange ratio (RER, g), hepatic glycogen (h), muscle glycogen (i), plasma total cholesterol (j), hepatic cholesterol (k), blood glucose (l), and glucose uptake measured by luciferase activity (m) in mice. The relative area under the curve (AUC) is shown in the inset (l). n = 15 male mice (a, d), n = 7 (WT) or 8 (MKO) male mice (b-g), n = 8 male mice (h-k), n = 10 female mice (l). n, Effect of feimin MKO on translocation of GLUT4 to the plasma membrane in Gastro and eWAT. Left panel shows representative immunostaining results; center and right panels show immunoblots and the corresponding quantification. Mice were refed for 1 hr after overnight fasting. ATP1A1, a plasma membrane protein, is used as a marker. TCL, total cell lysate; PM, plasma membrane fraction; LDM, low-density membrane fraction. Scale bars, 50 μm. n = 4 biological replicates. o, Effect of feimin MKO on the quantified AKT activation in liver, Gastro and eWAT extracts from WT and MKO mice (immunoblots from Fig. 1k). n = 6 biological replicates. p-s, Effect of feimin MKO on plasma triglycerides (TGs, p), hepatic TGs (q), tissue morphology evaluated by hematoxylin and eosin staining (r), and plasma insulin (s) in mice. cFeimin, cellular feimin. Scale bars, 50 μm. n = 8 male mice. t-u, Effect of high-fat diet (HFD) on body weight (t), glucose tolerance test (GTT) and insulin tolerance test (ITT) (u). The relative area under the curve (AUC) is shown in the inset. n = 8 male mice. v, Immunoblots and quantification data showing AKT activation in extracts of liver, Gastro and eWAT from male WT and feimin MKO mice fed with a HFD. Mice were refed for 1 hr after overnight fasting. Quantification of immunoblots is shown on the right. n = 6 biological replicates. Data are shown as mean ± s.e.m. Statistical comparisons were performed using an unpaired two-tailed Student’s t-test (a-d, h-l, n-q and s-v) or two-way ANOVA followed by Tukey’s test (e-g). All individual points and P values are shown.

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Extended Data Fig. 5 Evaluation of feimin levels in diabetic mice and humans.

a-b, Plasma insulin levels (a) and blood glucose levels (b) in male lean, diet-induced obese (DIO), ob/ob and db/db mice after overnight fasting (Fasted) or refeeding after overnight fasting (Refed). In refed mice, samples were collected 1 hr after the start of feeding. n = 6 mice. c-e, Plasma c-peptide levels (c), blood glucose levels (d) and ages (e) in normal and diabetic humans. Data are from 14 normal and 17 diabetic humans. Data are shown as mean ± s.e.m. Statistical comparisons were performed using an unpaired two-tailed Student’s t-test (e) or two-way ANOVA followed by Tukey’s test (a-d). All individual points and P values are shown.

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Extended Data Fig. 6 Feimin activates AKT and decreases blood glucose levels.

a-b, Effect of different doses of feimin on plasma feimin levels (a) or AKT activation (b) in extracts of mouse liver, Gastro and eWAT. Feimin (1 mg kg−1) was intraperitoneally injected for 45 min into overnight fasted mice. Quantification of immunoblots is shown on the right (b). n = 6 male mice (a), n = 6 biological replicates (b). c. Effect of feimin (1 mg kg−1), different dose of insulin, and a combination of feimin and insulin on AKT activation in extracts of male mouse liver, Gastro and eWAT. Quantification of immunoblots is shown on the right. n = 4 biological replicates. d, Plasma feimin levels after an intraperitoneal injection of 1 mg kg−1 His-tagged feimin. n = 5 male mice. e, Effect of a single injection (1 mg kg−1) and multiple injections of feimin (1 mg kg−1 per day for 5 or 21 consecutive days) on plasma insulin levels and blood glucose levels. n = 6 male mice. f. Effect of feimin (1 mg kg−1) and/or insulin (0.2 U kg−1) on AKT activation in extracts of mouse liver, Gastro and eWAT in lean female mice. Quantification of immunoblots is shown on the right. n = 4 biological replicates. Data are shown as mean ± s.e.m. Statistical comparisons were performed using two-way ANOVA followed by Tukey’s test (c and f) or unpaired two-tailed Student’s t-test (e). All individual points and P values are shown.

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Extended Data Fig. 7 Identification of MERTK as a receptor of feimin.

a-c, Immunoblots showing knockout of Mertk (a), Axl (b) or Tyro3 (c) in mice. The red arrows indicate the respective proteins. d-e, Immunostaining showing the effect of Axl knockout (d) or Tyro3 knockout (e) on feimin binding to frozen mouse tissue sections. 100 nM GST-feimin was incubated with frozen tissue slices. Scale bars, 20 μm. f, Coomassie staining showing SDS-PAGE separation of purified human GAS6, mouse feimin, MERTK (1-484 aa) and its mutant (Mut, E396R, D402R, D414R, E416R, E434R, E437R, E438R, D474R), AXL (1-428 aa) and TYRO3 (1-416 aa). Ex, the extracellular domain. g, Typical MST binding experiments showing the affinity between feimin and the extracellular domain (Ex) of AXL (1-428 aa) or TYRO3 (1-416 aa). Data are shown as mean ± s.e.m. n = 3 biological replicates. h, Deletion analysis to identify the regions in MERTK required for the feimin-MERTK interaction. Interaction-competent MERTK polypeptides are indicated by (+) in each schematic. IG, immunoglobulin-like domain; FNIII, fibronectin type III domain; TM, transmembrane domain; TK, tyrosine kinase domain. i-j, Alignment of the second FNIII domain of MERTK from different species (i) and protein structure of human MERTK (j) from AlphaFold. The positions of mutated amino acids are shown by the red arrows (i and j, right panel). k, GST pulldown assay showing the interaction between GST-feimin and MERTK-Flag or its mutant (Mut, E396R, D402R, D414R, E416R, E434R, E437R, E438R, D474R) in HEK293T cells. l, Typical MST binding experiments showing the affinity between GAS6 and the extracellular domain (Ex) of MERTK (1-484 aa) or its mutant (Mut, E396R, D402R, D414R, E416R, E434R, E437R, E438R, D474R). Data are shown as mean ± s.e.m. n = 3 biological replicates.

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Extended Data Fig. 8 Effect of Mertk knockout on metabolism.

a-m, Effect of Mertk knockout on body weight (a), food intake (b), water intake (c), fat mass ratio (d), movement (e), energy expenditure (f), respiratory exchange ratio (RER, g), hepatic glycogen (h), muscle glycogen (i), plasma total cholesterol (j), hepatic cholesterol (k), blood glucose (l), and glucose uptake measured by luciferase activity (m) in mice. The relative area under the curve (AUC) is shown in the inset (l). n = 7 male mice (a-g, j-k), n = 8 male mice (h-i), n = 10 female mice (l). n, Effect of Mertk knockout on translocation of GLUT4 to the plasma membrane in Gastro and eWAT. Left panel shows representative immunostaining results; center and right panels show immunoblots and the corresponding quantification. In these assays, mice were refed for 1 hr after overnight fasting. ATP1A1, a plasma membrane protein, is used as a marker. TCL, total cell lysate; PM, plasma membrane fraction; LDM, low-density membrane fraction. Scale bars, 50 μm. n = 4 biological replicates. o-r, Effect of Mertk knockout on plasma triglycerides (TGs, o), hepatic TGs (p), tissue morphology evaluated by hematoxylin and eosin staining (q), and plasma insulin (r) in mice. cFeimin, cellular feimin. Scale bars, 50 μm. n = 8 male mice. s, Quantification of immunoblots (Fig. 3k) showing AKT activation in liver, Gastro and eWAT extracts from Mertk+/+ and Mertk−/− mice. Mice were refed for 1 hr after overnight fasting. n = 6 biological replicates. t-u, Effect of high-fat diet (HFD) on body weight (t), glucose tolerance test (GTT) and insulin tolerance test (ITT) (u). The relative area under the curve (AUC) is shown in the inset. n = male 8 mice. v, Immunoblots and quantification showing AKT activation in extracts of liver, Gastro and eWAT from male Mertk+/+ and Mertk−/− mice fed with a HFD. Mice were refed for 1 hr after overnight fasting. Quantification of immunoblots is shown on the right. n = 6 biological replicates. w, Plasma Gas6 and Pros1 levels from male Mertk+/+ and Mertk−/− mice, or feimin WT and MKO mice. Mice were refed for 1 hr after overnight fasting. n = 6 mice. Data are shown as mean ± s.e.m. Statistical comparisons were performed using an unpaired two-tailed Student’s t-test (a-d, h-l, n-p and r-w) or two-way ANOVA followed by Tukey’s test (e-g). All individual points and P values are shown.

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Extended Data Fig. 9 Comparison of feimin and insulin signaling.

a, Glucose output or glucose uptake in mouse primary hepatocytes, myotubes or adipocytes. Cells were incubated in the presence or absence of 100 nM His-tagged feimin, 100 nM insulin (INS) or a combination of feimin and insulin. n = 6 biological replicates. b, Immunoblots showing INSRβ and AKT activation in extracts of liver, Gastro and eWAT from WT mice. Mice were given intraperitoneal injections of feimin (1 mg kg−1) or insulin (0.2 U kg−1) for 45 min after overnight fasting. Quantification of immunoblots is shown on the right. n = 4 biological replicates. c, Co-immunoprecipitation experiments indicate that there is no interaction between MERTK and INSR. However, MERTK interacts with itself, and this interaction is enhanced with feimin stimulation. d, Immunoblots showing AKT activation in extracts of liver, Gastro and eWAT from WT mice. Mice were injected with a MERTK inhibitor (10 mg kg−1, UNC2025) for 30 min and then feimin (1 mg kg−1) or insulin (0.2 U kg−1) for 45 min. Quantification of immunoblots is shown on the right. n = 4 biological replicates. Data are shown as mean ± s.e.m. Statistical comparisons were performed using two-way ANOVA followed by Tukey’s test (a, b, d). All individual points and P values are shown.

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Extended Data Fig. 10 Characterization of the rs7604639 SNP.

a, Summary of the basic parameters of the human subjects in this study. G allele, G/G; A allele, G/A and A/A. BMI, body mass index. OGTT, oral glucose tolerance test. b, Allele frequency of rs7604639 in the 1041 tested human subjects. c, Coomassie staining showing SDS-PAGE separation of purified human feimin, and the extracellular domain (Ex) of MERTK (1-484 aa) and its R466K mutant (1-484 aa). d, Glucose output or glucose uptake in human hepatocytes, myotubes or adipocytes. Cells were incubated in the presence or absence of 100 nM His-tagged feimin, 100 nM insulin or a combination of feimin and insulin. n = 6 biological replicates. Data are shown as mean ± s.e.m. Statistical comparisons were performed using unpaired two-tailed Student’s t-test (a) or two-way ANOVA followed by Tukey’s test (d). N/A, not applicable.

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Supplementary information

Reporting Summary

Supplementary Tables 1–6

Supplementary Table 1. Identification of feeding-induced secreted proteins by mass spectrometry. Supplementary Table 2. Characterization of secreted feimin by mass spectrometry. Supplementary Table 3. Parameters of human subjects involved in the fasting and refeeding programme. Supplementary Table 4. Parameters of normal and diabetic human subjects. Supplementary Table 5. Results of the siRNA library screen used to identify genes encoding proteins that modulate feimin binding on HEK293T cells. Supplementary Table 6. Parameters of human subjects involved in characterization of the rs7604639 SNP.

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Shi, X., Hu, X., Fang, X. et al. A feeding-induced myokine modulates glucose homeostasis. Nat Metab (2025). https://doi.org/10.1038/s42255-024-01175-9

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