Thermogenesis Is Limited by Cellular Competence

Aaron C Brown^1,2,3*

• ¹MaineHealth Institute for Research, Scarborough, United States
• ²The University of Maine, Orono, United States
• ³Tufts University School of Medicine, Boston, United States

Abstract Beige adipocytes have emerged as an attractive therapeutic target for metabolic disease due to their inducible thermogenic capacity and developmental plasticity. However, despite substantial advances in understanding the molecular pathways that activate thermogenesis, most thermogenic strategies have shown limited durability in pathological settings. This article integrates recent discoveries in adipocyte cell biology to argue that thermogenic failure reflects a loss of cellular competence rather than insufficient stimulation. We review emerging evidence demonstrating that mitochondrial capacity, intracellular signaling fidelity, and vesicle trafficking impose critical cell-intrinsic constraints on beige adipocyte function, particularly in obesity and aging. These insights highlight why chronic, systemic activation strategies often fail to produce sustained metabolic benefits. Drawing on principles from developmental biology, we propose that restoring thermogenic function will require precision control of adipocyte cell state, including spatially and temporally defined modulation of signaling pathways. Emerging technologies enabling reversible, cell-targeted control of adipocyte function, coupled with human cell-based models, offer new opportunities to overcome current limitations. Together, this perspective emphasizes that beige adipocytes are not merely thermogenic effectors, but dynamic cellular systems whose therapeutic potential depends on maintaining or restoring adaptive plasticity.