TOX3 in hypothalamic POMC-lineage cells regulates energy balance via the PTEN-AKT signaling axis

Although the hypothalamus is well-established as the central regulator of energy homeostasis through specialized neuronal circuits, the molecular mechanisms governing these pathways remain incompletely elucidated. In this study, we identify thymocyte selection-associated high mobility group box 3 (TOX3) as a critical metabolic regulator in pro-opiomelanocortin (POMC) neurons of the arcuate nucleus.

By employing cell-type-specific genetic manipulation in murine models, we establish that conditional TOX3 ablation in POMC neurons exacerbates diet-induced obesity and metabolic dysfunction, while its overexpression in these neurons confers robust metabolic benefits. Mechanistically, TOX3 enhances POMC neuronal function via a novel post-translational regulatory mechanism involving PTEN proteasomal degradation, leading to potentiated AKT signaling.