Transcriptomic and metabolomic profiles reveal the functions of IGF-1 c.258 A > G synonymous mutation in milk fat content

Jiayuan Fang; Shuo Zheng; Xunming Zhang; Xi Chen; Yi Li; Libo Zhang; Xingyu Xiao; Yunyun Cheng; Yuanyuan Xu; Linlin Hao

doi:10.1016/j.jare.2025.06.086

Transcriptomic and metabolomic profiles reveal the functions of IGF-1 c.258 A > G synonymous mutation in milk fat content

J Adv Res. 2025 Jun 28:S2090-1232(25)00496-5. doi: 10.1016/j.jare.2025.06.086. Online ahead of print.

Authors

Jiayuan Fang¹, Shuo Zheng¹, Xunming Zhang¹, Xi Chen¹, Yi Li¹, Libo Zhang¹, Xingyu Xiao¹, Yunyun Cheng², Yuanyuan Xu³, Linlin Hao⁴

Affiliations

¹ College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, Jilin 130062, China.
² NHC Key Laboratory of Radiobiology, College of Public Health, Jilin University, Changchun 130021, China.
³ College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, Jilin 130062, China. Electronic address: xuyuan@jlu.edu.cn.
⁴ College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, Jilin 130062, China. Electronic address: haolinlin@jlu.edu.cn.

PMID: 40588029
DOI: 10.1016/j.jare.2025.06.086

Abstract

Introduction: Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous mutation c.258 A > G (rs322131043) in IGF-1, which influenced IGF-1 expression and caused differences in metabolism.

Objectives: This study aims to reveal a new regulatory function of IGF-1 c.258 A > G on milk fat metabolism.

Methods: Livers transcriptomics was used to identify differentially expressed genes between wild type mice (WT) and IGF-1 c.258 A > G mice (Homozygous mutation, Ho). Subsequently, lipid phenotyping, followed by metabolomics of mammary glands was conducted to verify transcriptomic findings. Finally, the potential mechanisms underlying IGF-1 c.258 A > G-induced changes in milk fat metabolism were explored though integrated transcriptomics-metabolomics analysis and Western blot validation.

Results: IGF-1 c.258 A > G changed the expression of genes related to lipid metabolism in livers of 8-week-old mice, including a 10-fold ‌lipoprotein lipase (LPL) expression (P < 0.01) and ‌80-90 % downregulation of acyl-CoA thioesterase 3 (Acot3), enoyl-Coenzyme A delta isomerase 3 (Eci3), fatty acid synthase (FASN), and sterol regulatory element binding protein1 (SREBP1) expression (P < 0.01). The milk fat content of Ho dams on the second day of lactation (L2D) was decreased 50 % than that of WT dams (P < 0.05), although there was no significant difference in adipose tissue of 8-week-old WT/Ho mice. The levels of triglycerides, sphingolipids and their related fatty acyl chains (10:0, 26:0, 14:2, 20:4, 11:3, 19:0) in mammary glands of L2D Ho dams were reduced 10-50 % observed by lipid metabolomics. And combined with transcriptomics and Western blot, the data suggested that a ‌2.5-fold upregulation of LPL expression‌ (P < 0.05) may contribute to the milk fat metabolism changes mediated by the ‌ IGF-1 c.258 A > G.

Conclusion: This study revealed new function of IGF-1 c.258 A > G on milk fat metabolism, thereby informing the development of targeted genetic breeding on milk fat trait.

Keywords: LPL; Lipid; Mammary glands; SNP; Triglyceride.