Purpose Adipocyte glucocorticoid (GC) signalling influences lipid storage and insulin sensitivity, and South Asians develop insulin resistance at lower BMI than White Europeans. We tested whether early modest weight gain alters adipocyte GC-related transcripts differently by ancestry and whether within-person transcript changes track dynamic insulin responses.Methods White European (n = 21) and South Asian (n = 14) men underwent ~ 6% diet-induced weight gain. Abdominal subcutaneous adipocytes were sampled at baseline and post–weight gain for RT-qPCR assessment of GC-responsive transcripts (FKBP5, TSC22D3/GILZ) and related targets (HSD11B1, HSD11B2, IL2, IL6). Metabolic responses were characterised using a standardised mixed-meal test with 5-hour profiles of glucose, insulin, C-peptide and triglycerides; hepatic triglyceride content was quantified by MRI.Results Weight gain reduced FKBP5 (− 23.65 ± 8.82% in White Europeans; −17.68 ± 11.62% in South Asians; P = 0.007) and GILZ (− 11.40 ± 2.83%; −5.95 ± 4.01%; P = 0.001 for change with weight gain), with no ethnicity×intervention interaction (P ≥ 0.26). HSD11B1/HSD11B2 and IL2/IL6 did not change. At baseline, FKBP5 and GILZ were associated with adiposity, liver fat and adipocyte size. Within-person ΔFKBP5 (post–weight gain minus baseline) correlated with Δpostprandial insulin (r = 0.46, P = 0.006) and ΔC-peptide (r = 0.34, P = 0.049). ΔGILZ correlated with Δfasting glucose (r = − 0.40, P = 0.017) and Δpostprandial insulin (r = 0.34, P = 0.049). In mixed-effects models, change in postprandial insulin remained an independent correlate of both transcripts.Conclusion Early modest weight gain downregulates adipocyte GC-responsive transcripts similarly across ancestries, and dynamic transcript changes track insulin exposure. These findings implicate insulin dynamics as a potential driver of adipocyte GC signalling adaptations during early weight gain, linking adipocyte transcriptional responses to clinically relevant postprandial insulin physiology.