Suprachiasmatic nucleus regulation of brown fat thermogenesis via ADRB3-S100B axis

The suprachiasmatic nucleus (SCN), the central circadian pacemaker, orchestrates daily metabolic rhythms, yet its role in substrate selection and thermogenic adaptation remains insufficiently understood. Here, we show that SCN lesioning abolishes the adaptive suppression of brown adipose tissue (BAT) thermogenesis typically observed during time-restricted feeding in subthermoneutral environments (TRF-STE), a condition that imposes concurrent nutrient and thermal challenges. Contrary to wild-type responses, SCN-lesioned mice maintain elevated BAT thermogenic activity, driven by enhanced sympathetic tone and β3-adrenergic receptor (ADRB3) signaling. This compensatory response promotes a shift from lipid oxidation to glucose utilization, enabling heat production despite impaired lipolysis. Mechanistically, we identify a SCN-regulated ADRB3-S100B signaling axis underlying this metabolic reprogramming. S100B, a nutrient-sensitive protein calcium-binding protein, is upregulated in BAT following SCN disruption, where it enhances thermogenic capacity by stimulating brown adipocyte proliferation and suppressing senescence. Functional studies reveal that S100B is both necessary and sufficient for sustaining BAT thermogenesis under TRF-STE. Furthermore, diverse SCN disruption models, including light-induced circadian arrhythmia, N - Methyl - D - aspartic acid (NMDA) excitotoxicity, and Caspase-3-mediated ablation, consistently elevates S100B expression in BAT, reinforcing its role as a convergent effector of SCN-regulated metabolic adaptation. These findings uncover a previously unrecognized role of the SCN in coordinating thermogenic flexibility and fuel partitioning under stress. The identification of the ADRB3-S100B axis as a key mediator of this adaptation provides new mechanistic insight into the neural regulation of energy balance, with potential therapeutic relevance for circadian misalignment, obesity, and resistance to diet-induced weight loss.