Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis

Bariatric surgery improves hyperglycemia in obesity and type 2 diabetes (T2D), yet its central mechanisms remain unclear. Through cerebrospinal fluid proteomic profiling of rats, we identify reduced central malate dehydrogenase 2 (MDH2) levels that correlate with surgery-induced restoration of normoglycemia. Central MDH2 blockade with the selective antagonist LW6 attenuates hyperglycemia under high-glucose conditions, independent of its enzymatic activity. Mechanistically, MDH2 inhibition activates oxytocinergic neurons in the hypothalamic paraventricular nucleus (PVN), promoting glucose disposal via sympathetic activation of brown adipose tissue (BAT) thermogenesis. Chemogenetic activation of PVN oxytocin neurons recapitulates this effect, while their silencing, oxytocin receptor blockade, or sympathetic inhibition abolishes LW6's metabolic benefits. PVN-specific Mdh2 deletion abrogates LW6's glucose-lowering effects and impairs systemic glucose homeostasis. LW6 demonstrates robust long-lasting glucose-lowering effects in a T2D mouse model. These findings establish MDH2 as a central glucose modulator and therapeutic target linking hypothalamic signaling to peripheral energy metabolism via an oxytocin-sympathetic nervous system (SNS)-BAT axis.