THYROID HORMONE-INHIBITED MEDULLARY RAPHE NEURONS THAT CONTROL METABOLIC HOMEOSTASIS

Metabolic homeostasis requires continuous alignment of peripheral tissue activity with internal energy state. The medullary raphe transmits peripheral autonomic responses to acute external stressors, yet energy-state sensing and metabolic regulation of this primary sympathetic premotor region remain undefined. Here, we identify medullary raphe neurons expressing thyrotropin-releasing hormone (Trh) as interoceptive effectors essential for dynamically coordinating sympathetic outflow to metabolically relevant tissues. Energy deprivation activates Trh, but not other medullary raphe premotor neurons, to promote lipolysis in white adipose tissue, hepatic gluconeogenesis, and preserve brown adipose tissue thermogenesis. Leptin-regulated negative feedback of the hypothalamic-pituitary-thyroid axis gradually gates the activity of Trh neurons, which are inhibited by thyroid hormone, and exert sustained excitatory control of spinal sympathetic output neurons through serotonin release. Our findings introduce Trh neurons of the medullary raphe as critical coordinators of systemic metabolism and reveal a neurohormonal feedback circuit that continuously aligns sympathetic output with internal energy state.