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

Obesity and its associated metabolic disorders, including type 2 diabetes and fatty liver disease, represent a growing global health burden. 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 hypothalamic pro-opiomelanocortin (POMC)-lineage cells in mice. By employing cell-type-specific genetic manipulation in murine models, we establish that conditional TOX3 ablation in POMC-lineage cells exacerbates diet-induced obesity and metabolic dysfunction, while its overexpression in these neurons confers robust metabolic benefits. Mechanistically, TOX3 enhances the function of POMC-lineage cells through a post-translational regulatory mechanism involving PTEN proteasomal degradation, leading to potentiated AKT signaling. This central modulation drives sympathetic activation of brown adipose tissues, resulting in enhanced thermogenesis and energy expenditure. Notably, TOX3 exhibits striking neuronal specificity, as both loss- and gain-of-function manipulation in agouti-related peptide (AgRP) neurons produce negligible metabolic consequences. Our work identifies previously unrecognized physiological roles of TOX3 in POMC-lineage cells that are essential for maintaining energy homeostasis in mice, thereby revealing therapeutic opportunities for metabolic disorders. Hypothalamic POMC neurons are critical for energy balance. Here, authors show that TOX3 in these neurons regulates metabolism by promoting PTEN degradation and AKT activation, enhancing thermogenesis to protect against obesity.