Parathyroid Hormone Receptor Signaling in AgRP Neurons Controls Energy Metabolism

Abstract

A fundamental component of the central control of energy metabolism by the brain is the ability of the hypothalamic neurons to accurately integrate hormones that modulate the needs of various organs in energy fuel. Exploring the impact of novel body-brain interactions is essential to better understand the complex mechanisms that regulate whole-body metabolism in physiological and pathophysiological context. 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 discover the role of the parathyroid hormone (PTH) receptor 1 pathway, a master regulator of calcium ion biochemistry and bone formation, in brain “hunger” Agouti-related peptide (AgRP) neurons that operates a ligand-specific bimodal control of either feeding behaviour, energy expenditure, fat oxidation or nutrient partitioning. These complementary but distinct metabolic outputs rely on the capacity of two cognate endocrine and paracrine ligands, PTH and PTH-related peptide (PTHrP), to activate segregated intracellular kinases activation and lipophagic processes, that ultimately produce convergent but distinct physiological outputs. Our results reveal that the parathyroid hormonal system, acts as a fine-tuning mechanism in specialized neuronal circuits controlling the integration of systemic metabolic signals, allowing for hypothalamic adaptive responses to energy demands. These findings may offer novel promising target of therapeutic intervention for obesity and related metabolic disorders.