Subcutaneous adipocyte glucocorticoid-responsive transcripts after modest weight gain in South Asian and White European men: an exploratory longitudinal study

Abstract Aims/hypothesis Adipocyte glucocorticoid (GC)-responsive transcripts are linked to lipid storage and insulin sensitivity, and South Asians develop insulin resistance at lower BMI than White Europeans. We tested whether modest short-term weight gain was associated with adipocyte GC-related transcripts differently by ancestry and whether within-person transcript changes were associated with dynamic insulin responses. Methods In this exploratory secondary analysis of the GlasVEGAS study, White European ( n = 21) and South Asian ( n = 14) men underwent ~ 6% diet-induced weight gain. Isolated abdominal subcutaneous adipocytes were sampled at baseline and post-weight gain for RT-qPCR assessment of GC-responsive transcripts and related targets. Metabolic responses were characterised using a standardised mixed-meal test with 5 h profiles of glucose, insulin, C-peptide and triglycerides; hepatic triacylglycerol 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 TSC22D3 (also known as 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 Δ FKBP5 (post-weight gain minus baseline) correlated with Δpostprandial insulin ( r = 0.46, p = 0.006) and ΔC-peptide ( r = 0.34, p = 0.049). Δ GILZ correlated with Δfasting glucose ( r = − 0.40, p = 0.017) and Δpostprandial insulin ( r = 0.34, p = 0.049). In exploratory within-person analyses, changes in FKBP5 and GILZ were associated with changes in postprandial insulin-related measures. Conclusion/interpretation Early modest weight gain downregulates adipocyte GC-responsive transcripts, with no statistically significant ethnicity-by-weight gain interaction detected in this modest-sized exploratory cohort, and dynamic transcript changes track insulin exposure. These findings implicate a potential link between dynamic insulin responses and adipocyte glucocorticoid-responsive transcription during early weight gain, linking adipocyte transcriptional responses to clinically relevant postprandial insulin physiology.