Developmental versus diet-induced obesity: similar fat expansion, divergent molecular fingerprints in adipocyte progenitors

Objective Preclinical models have been instrumental in elucidating the mechanisms underlying obesity and its metabolic complications. However, most studies rely on high-fat diet (HFD) feeding, which primarily models adult-onset obesity driven by excessive caloric intake from fat. Consequently, other forms of obesity—particularly those originating during development—remain underexplored. Here, we investigated whether developmental and diet-induced obesity engage distinct molecular programs in adipocyte progenitor cells (APCs), despite producing similar adipose tissue expansion. Methods We analyzed the transcriptome of APCs from inguinal (iWAT) and epididymal (eWAT) depots in murine models of developmental obesity induced by litter size reduction (SL) and adult-onset obesity induced by HFD. A combined model (SL-HFD) was also evaluated to assess the long-term impact of early overnutrition on adult dietary responses. Results Both models led to comparable adipocyte hypertrophy without significant changes in canonical lipogenic or adipogenic genes. However, Dlk1 and Wisp2 —inhibitors of preadipocyte commitment—were consistently upregulated. Transcriptomic profiling revealed divergent molecular signatures: developmental obesity suppressed immune-related pathways in iWAT, whereas diet-induced obesity activated cholesterol metabolism, immune regulation, and extracellular matrix remodeling, especially in eWAT. The SL-HFD condition induced a unique, non-additive transcriptional program, defining a distinct molecular state. Conclusions Developmental and diet-induced obesity are mechanistically distinct yet phenotypically convergent. The timing of obesity onset imprints lasting, depot-specific transcriptional programs in APCs that shape adipose plasticity and responses to later nutritional stress. These findings highlight the need to diversify preclinical models to capture the heterogeneity of obesity.