Active whitening of human SGBS adipocytes is associated with coordinated AMPK–HIF–autophagy signalling and mitochondrial remodelling

Adipocyte whitening is a late-stage phenotypic transition that follows transient browning; however, its cellular and molecular basis remains incompletely understood. In particular, it is debated whether whitening reflects a passive loss of thermogenic identity or an actively regulated adaptive state. Late-stage whitening was investigated in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes using an integrated approach combining quantitative mitochondrial morphology, lipid droplet remodelling, transcriptomics, protein analyses, and network-based bioinformatics. Whitening was characterised by coordinated suppression of thermogenic and oxidative gene programmes, together with enrichment of pathways associated with AMPK signalling, hypoxia response, and autophagy. Quantitative imaging analyses revealed stabilisation and remodelling of the mitochondrial network, with features consistent with mitochondrial quality control rather than degenerative loss of function. Transcriptomic and network analyses further supported the enrichment of autophagy-related processes and stress-adaptive signalling during the late stages of differentiation. Overall, these findings indicate that adipocyte whitening is an actively regulated adaptive cellular state, integrating mitochondrial structural remodelling with metabolic and stress-responsive signalling. These results provide a conceptual framework for understanding adipocyte phenotypic plasticity during late differentiation. Created in BioRender. Venerando, A. (2026) https://BioRender.com/rtkfeho . • Demonstrates whitening as an active metabolic adaptation rather than passive regression • Associates coordinated AMPK–HIF–autophagy pathway engagement with adipocyte whitening • Shows mitochondrial network stabilization and autophagy-associated remodelling • Reveals coordinated suppression of PPAR/oxidative thermogenesis at late differentiation • Proposes whitening as an energy-preserving cellular strategy rather than thermogenic failure