Adipocyte‐specific IGF1R knockout activates the β‐catenin/apelin axis to combat diet‐induced obesity in male mice

Abstract Aims Obesity, driven by complex genetic and environmental interactions, remains a global health crisis with limited therapeutic options. The insulin‐like growth factor 1 receptor (IGF1R) plays dual roles in metabolism and growth, but its tissue‐specific functions in adipose biology are controversial. This study investigates how adipose‐specific IGF1R knockout impacts systemic metabolism under high‐fat diet (HFD) stress and explores the underlying mechanisms. Methods Adipose‐specific IGF1R knockout mice ( AdIGF1RKO ) were generated by crossing Igf1r fl/fl mice with Adipoq‐Cre transgenics. Mice were fed a normal chow diet (NCD) or HFD for 20 weeks. Metabolic phenotyping included glucose/insulin tolerance tests, body composition analysis and serum profiling. RNA‐seq, Western blot and quantitative real‐time reverse transcriptase PCR were used to identify molecular pathways. In vitro studies with stromal vascular fraction (SVF) cells validated β‐catenin/apelin interactions. Results AdIGF1RKO male mice exhibited reduced adipose mass under NCD and resisted HFD‐induced obesity, showing attenuated hepatic lipid deposition and improved glucose metabolism. Mechanistically, IGF1R knockout enhanced INSR and Akt phosphorylation, driving GSK3β‐β‐catenin activation and apelin upregulation. Apelin activated AMPK, suppressing lipogenesis and enhancing fatty acid oxidation. Notably, β‐catenin's role shifted from inhibiting adipogenesis in precursors to promoting metabolic adaptation in mature adipocytes. Conclusion We unveil a β‐catenin/apelin‐driven endocrine axis that reprograms energy metabolism under obesogenic stress. Therapeutically, targeting adipose IGF1R or apelin signalling could combat obesity while avoiding systemic toxicity. Limitations include unresolved β‐catenin/Apln transcriptional mechanisms, APJ function and tissue‐specific AMPK effects. Our findings redefine IGF1R's metabolic role and propose novel strategies for obesity‐related disorders.