Adropin: The Metabolic Hormone Rewiring the Map of Chronic Disease

Few molecules discovered in the past two decades have traveled as far, scientifically, as adropin. First identified in 2008 as a secreted peptide that links dietary macronutrient intake to energy balance and lipid metabolism, this 76-amino-acid hormone, encoded by the energy homeostasis-associated gene ENHO, was initially cast as a player in the narrow drama of obesity and insulin resistance. A comprehensive new review published in Molecular Biology Reports argues that this framing is now obsolete. Drawing together evidence from cell biology, animal models, and human cohort studies, the authors present adropin as a pleiotropic endocrine signal whose influence extends from the liver and skeletal muscle to the endothelium, the brain, the immune system, and the fibrotic stroma of chronically inflamed organs. In doing so, they also deliver a sobering assessment of how much of the field rests on solid ground, and how much remains conjecture.

The review’s central organizing principle is a distinction between metabolic and non-metabolic disease evidence, an approach the authors pair with an explicit evidence map that separates direct findings, indirect inferences, and genuine controversy for every receptor and signaling pathway they discuss. This is a rare level of methodological candor in a literature that has grown rapidly and, at times, unevenly. Circulating adropin concentrations are typically reduced in obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, atherosclerosis, heart failure, cognitive aging, and several fibrotic and reproductive disorders. Yet the picture is not uniformly one-directional: diabetic kidney disease and certain acute stress states show the opposite pattern, with adropin levels rising rather than falling. That bidirectionality, the authors contend, is not a nuisance artifact but a genuine constraint on how the peptide can be deployed therapeutically.

At the molecular level, adropin’s actions converge on two cell-surface partners: the orphan G-protein-coupled receptor GPR19 and the GPI-anchored neuronal protein NB-3, also known as contactin-6. These initiators trigger overlapping but tissue-specific cascades, including the AMPK/ACC axis governing fatty acid oxidation, the PI3K/Akt/eNOS pathway that sustains endothelial nitric oxide production, a GPR19/MAPK/PDK4 module that reshapes mitochondrial fuel selection in the heart, the Notch1/Hes1 cascade that preserves blood-brain barrier integrity, and the TGF-β/GLI1 pathway through which adropin restrains fibroblast activation. The elegance of this architecture lies in its economy: a single circulating peptide, acting through a small set of receptors, coordinates glucose utilization, vascular tone, mitochondrial substrate preference, and tissue remodeling across organ systems that clinical medicine usually treats in isolation.

The metabolic evidence remains the deepest stratum. In diet-induced obese mice, adropin administration improves glucose tolerance and shifts substrate utilization toward lipid oxidation, effects traced to regulation of hepatic glucose production and pyruvate dehydrogenase activity in cardiac and skeletal muscle. Human observational studies reinforce the association: fasting plasma adropin correlates with dietary fat intake, falls with obesity and aging, and rises after gastric bypass surgery. Low circulating adropin in male nonhuman primates predicts vulnerability to weight gain and metabolic dysregulation on a high-sugar diet, a finding that moves the association beyond correlation in a tightly controlled model. Daily adropin treatment in mice with type 2 diabetes improves the glucolipid profile, reduces hepatic lipid content, and normalizes elevated liver enzymes, while expression studies show that hepatocyte adropin responds to caloric restriction and tracks circadian, lipoprotein, and mitochondrial processes in human tissues.

The cardiovascular and neurological extensions of adropin biology are where the review’s translational ambitions become most visible. In the vasculature, adropin increases endothelial nitric oxide bioavailability, suppresses monocyte adhesion to endothelial cells, restrains vascular smooth muscle proliferation during neointimal hyperplasia via AMPK/ACC signaling, and slows atherosclerosis in double-knockout mice by regulating endothelial-to-mesenchymal transition. In the heart, it improves cardiac efficiency by optimizing mitochondrial fuel selection and protects against remodeling in models of heart failure with preserved ejection fraction, partly through mitigation of oxidative stress via Nrf2/HO-1 signaling. Recent work also implicates adropin in calcium-handling dysregulation of coronary disease, connecting the peptide to SERCA2b and S100A1 pathways. In the brain, adropin preserves blood-brain barrier integrity through Notch1/Hes1 signaling after intracerebral hemorrhage, protects the neurovasculature in ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism, and correlates with cognitive performance in aging humans and rhesus macaques, with synthetic adropin improving cognitive function in aged mice.

Perhaps the most surprising chapters concern fibrosis, reproduction, and immunity. In systemic sclerosis, adropin attenuates fibroblast activation and fibrosis by repressing TGF-β/GLI1 signaling, a result highlighted in Nature Reviews Rheumatology as a potential new axis for antifibrotic therapy. In polycystic ovary syndrome, adropin ameliorates reproductive dysfunction in mouse models, promoting adipose tissue browning and M2 macrophage polarization, an immunometabolic mechanism that links ovarian pathology to systemic energy balance. In cancer, the story turns cautionary: low-dose adropin stimulates inflammasome activation in macrophages via mitochondrial reactive oxygen species in colorectal cancer progression, and dose-dependent immunomodulatory effects complicate any simple narrative of adropin as protective. The review treats these contradictions honestly, flagging tumor immunity and kidney injury as contexts where the therapeutic window may be narrow or bidirectional.

Central control of feeding adds another layer. Experiments in neonatal broiler chicks show that central adropin injection modulates feeding behavior through neuropeptide Y and melanocortin pathways, while earlier work demonstrated that adropin acts in the brain to inhibit water drinking, potentially through GPR19 in circumventricular organs, with hypoxia-induced antidipsogenic effects mediated by TRPV4-CaMKK-AMPK signaling. These findings position adropin as a neurohormone as much as a metabolic hormone, a duality the review’s authors emphasize in arguing that peripheral and central adropin systems must be studied as integrated but distinct circuits. Sex differences add further complexity: estrogen receptor alpha-dependent regulation of adropin predicts divergent liver responses to high-fat diet between sexes, and expression studies in reproductive organs suggest endocrine roles beyond energy homeostasis.

Yet the review is unsparing about the field’s structural weaknesses. Adropin is an unstable peptide, and delivering it across the blood-brain barrier remains unsolved. Immunoassays for circulating adropin are not standardized, which undermines comparability across the many observational studies that now populate the literature, although a newly developed specific competitive ELISA for plasma adropin represents a step toward harmonization. Receptor pharmacology is incomplete: GPR19 remains formally orphan, and the relative contribution of NB-3/CNTN6 versus GPR19 in any given tissue is largely unresolved. The authors argue, pointedly, that further disease associations will not advance the field; progress now depends on receptor definition, assay harmonization, and delivery chemistry. Biomarker interpretation also demands care, since low adropin predicts atrial fibrillation and asymptomatic heart failure in diabetes independently of natriuretic peptides, yet elevated levels in diabetic kidney disease may reflect stress responses rather than protection.

The verdict that emerges is one of disciplined optimism. Adropin has earned its place as a genuine integrator of metabolism, vascular biology, neurobiology, and immunity, with mechanistic data in cells and animals that are often compelling and human evidence that is consistently associative but increasingly broad. What separates adropin from the long list of candidate hormones that have faded after an initial burst of enthusiasm is the specificity of its signaling map and the honesty of the accounting now attached to it. If receptor pharmacology matures, if assays are standardized, and if peptide engineering solves stability and delivery, adropin could move from biomarker panels to the clinic in cardiometabolic disease, stroke, and fibrosis. Until then, the peptide that once seemed to merely report on what we eat now stands revealed as a molecular hinge connecting diet, circadian biology, and the chronic diseases of modern life, and the race to drug it has only just begun.

Subject of Research: Adropin signaling pathways and their roles in metabolic and non-metabolic disorders

Article Title: Adropin signaling pathways in metabolic and non-metabolic disorders

Article References: Valizadeh, A., Mohammadian, J., Ebadi, A., Ahmadi, B., Danaiyan, S., Meghrazi, K., & Ghorbanihaghjo, A. (2026). Adropin signaling pathways in metabolic and non-metabolic disorders. Molecular Biology Reports, 53(1), Article 1709. https://doi.org/10.1007/s11033-026-12896-3

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12896-3

Keywords: adropin, ENHO, GPR19, AMPK, PI3K/Akt/eNOS, TGF-β/GLI1, insulin resistance, atherosclerosis, blood-brain barrier, fibrosis, biomarker, peptide hormone