Advances in adropin-mediated signaling pathways and molecular mechanisms: Receptor controversies, tissue-specific evidence, and emerging physiological roles.

BACKGROUND

Adropin, a 76-amino-acid peptide encoded by ENHO, is involved in metabolic balance, endothelial function, and inflammatory regulation. It has been linked to PI3K/Akt, MAPK/ERK1/2, AMPK, Notch, and redox/inflammatory pathways, although the identity of a dedicated receptor and the extent to which these mechanisms are conserved across tissues remain unresolved.

OBJECTIVES

This review summarizes adropin signaling insights, critically evaluates the strength and limitations of the available evidence, and examines emerging endocrine and reproductive roles.

METHODS

We reviewed primary in vitro, ex vivo, animal, and human studies, with particular attention to species/cell model, pathway-specific perturbation, direct biochemical readouts, conflicting findings, and human validation.

RESULTS

Adropin activates VEGFR2-dependent Akt/ERK/eNOS signaling in endothelial cells and enhances insulin-stimulated Akt signaling and cell-surface GLUT4 in skeletal muscle. In the liver, PP2A/AMPK signaling provides strong mechanistic support for suppression of hepatic glucose production. NB-3/Notch signaling is best supported in neural models, whereas GPR19 remains a putative, disputed receptor candidate. Importantly, skeletal-muscle AMPK activation is not universal, direct adipose AMPK activation remains unproven, and pancreatic and reproductive effects are context dependent.

CONCLUSIONS

Adropin is a versatile regulator connecting energy metabolism, vascular biology, neural function, redox homeostasis, and emerging endocrine/reproductive processes. Current evidence supports a tissue- and model-dependent signaling network rather than a single universal receptor-pathway cascade.