Adropin signaling pathways in metabolic and non-metabolic disorders

Adropin is a secreted 76-amino-acid peptide encoded by the energy homeostasis-associated gene ENHO. First identified in 2008 as a nutrient-responsive signal linking macronutrient intake with energy balance and lipid metabolism, it is now recognized as a pleiotropic hormone with actions extending well beyond classical metabolic tissues. Circulating adropin is typically reduced in obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, atherosclerosis, heart failure, cognitive aging, and several fibrotic and reproductive disorders. However, diabetic kidney disease and some acute stress states show the opposite pattern. Two cell-surface partners, the orphan G-protein-coupled receptor GPR19 and the GPI-anchored neuronal protein NB-3/CNTN6, initiate overlapping but tissue-specific cascades: AMPK/ACC, PI3K/Akt/eNOS, GPR19/MAPK/PDK4, Notch1/Hes1, and TGF-β/GLI1. Through these pathways, adropin improves insulin action and mitochondrial fuel selection, increases endothelial nitric oxide bioavailability, restrains vascular remodeling, preserves blood-brain barrier integrity, and represses fibroblast activation. This review (i) separates metabolic from non-metabolic disease evidence, (ii) introduces an explicit evidence map distinguishing direct evidence, indirect evidence, and genuine controversy for every receptor and pathway, (iii) adds dedicated coverage of central feeding control, calcium-handling dysregulation in coronary disease, TGF-β/GLI1 signaling, biomarker interpretation, and translational pharmacology, and (iv) argues that progress now depends on receptor definition, assay harmonization, and delivery chemistry rather than on further disease associations. Remaining barriers include peptide instability, blood-brain-barrier delivery, non-standardized immunoassays, incomplete receptor pharmacology, and a narrow or bidirectional therapeutic window in kidney injury and tumor immunity.