Background <p>Breast cancer cells that break through the basement membrane interact directly with neighboring adipocytes. Therefore, adipocytes adjacent to the invasive front of tumour undergo lipolysis and transform into cancer-associated adipocytes (CAAs), which is vital for the malignant progression of breast cancer. However, tumor-derived factors that trigger this process are still to be determined.</p> Methods <p>Transcriptome sequencing was used to identify the downstream transcription factor of adrenomedullin (AM). Tet-On system was used to construct the 3T3-L1 cell line with inducible overexpression of Zeb1. Adipocyte-specific knock-in Zeb1 transgenic mice (<i>Zeb1</i>^<i>adiTG</i>) were used to construct an allograft tumor model.</p> Results <p>Breast cancer cell-derived AM downregulated the transcriptional expression of Zeb1 by triggering the cAMP/PKA/Creb1 pathway, thereby exerting lipolytic effects in CAAs. On the contrary, adipose tissue-specific upregulation of Zeb1 significantly attenuated AM-induced lipolytic phenotypes. Of note, we used the <i>Zeb1</i>^<i>adiTG</i> mice to construct allograft tumor models. The results confirmed that breast cancer cell-derived AM conferred tumorigenicity in vivo, which effect was predominantly dependent on the aberrant expression of adipocyte-specific Zeb1.</p> Conclusions <p>These findings collectively suggested that breast cancer cell-derived AM promotes lipid metabolic reprogramming through a Zeb1-dependent manner in CAAs, which displays significant clinical implications and may provide promising therapeutic approaches for targeting the breast cancer-associated adipose microenvironment.</p>