Parathyroid Hormone Receptor 1 Signaling Encodes Multifaceted Metabolic Programs in AgRP Neurons

Abstract

Organisms continuously adapt food intake and nutrient utilization to fluctuating energy demands, requiring the brain to accurately integrate signals coming from diverse metabolic organs and local signals into distinct physiological responses. How hypothalamic neurons discriminate these signals to independently regulate feeding behavior and peripheral metabolism remains poorly understood. In recent years, a coordinated regulation between bone physiology and the central control of energy metabolism has emerged, opening questions about potential common hormonal networks and signaling pathways between the bone and the brain. Here, we identify parathyroid hormone receptor 1 (PTH1R) signaling, a master regulator of calcium ion biochemistry and bone formation, in Agouti-related peptide (AgRP) neurons as an unexpected neuroendocrine mechanism for the control of feeding behaviourand nutrient partitioning. the two cognate endocrine and paracrine ligands, PTH and PTH-related peptide (PTHrP), selectively activat segregated intracellular kinases activation and lipophagic processes in AgRP neuron, ultimately producing convergent physiological outputs. Together, our findings identify the parathyroid hormonal system acts as a fine-tuning mechanism in specialized neuronal circuits allowing for hypothalamic adaptive responses to energy demands and systemic metabolic signals. Keywords: Parathyroid hormone-related peptide (PTHrP), hypothalamus, arcuate nucleus, agouti-related peptide neurons, energy metabolism, fasting, autophagy, free fatty acids