Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy

Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to a lack of experimental approaches to directly manipulate cell size. Here, we establish methods to isolate and culture large and small primary adipocytes from the same adipose tissue, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size—rather than body weight—drives distinct phenotypic cell states. Notably, large adipocytes increase lipid release mediated by elevated secretion of extracellular vesicles. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of neighboring breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides and dyslipidemia independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression. Overall design: RNA sequencing of size-sorted mammary adipocytes isolated from both diet-induced and genetic mouse models of obesity. Four to five biological replicates are included per condition.