Adropin

Adropin shifts cellular fuel preference toward glucose oxidation over fatty acid oxidation. It suppresses pyruvate dehydrogenase kinase 4 (PDK4), which normally phosphorylates and inactivates pyruvate dehydrogenase (PDH). By keeping PDH active, adropin allows pyruvate to enter the TCA cycle as acetyl-CoA, enhancing glucose oxidation. This effect reduces the Randle cycle competition between glucose and fatty acids, improving whole-body glucose utilization.

Adropin activates endothelial nitric oxide synthase (eNOS) through PI3K/Akt phosphorylation, increasing NO bioavailability and reducing vascular inflammation. It reduces oxidized LDL-induced endothelial dysfunction, lowers ICAM-1 and VCAM-1 expression, and inhibits monocyte adhesion. In models of cerebral ischemia, adropin reduces infarct volume and preserves blood-brain barrier integrity through eNOS-dependent mechanisms.

ENHO is highly expressed in the brain, particularly in neurons and astrocytes. Adropin improves cognitive function in aging mice, enhancing spatial learning and memory. It reduces neuroinflammation (lower IL-1b, TNF-alpha in brain), promotes neurotrophic signaling (BDNF, CREB phosphorylation), and protects against oxidative stress. Central adropin may also modulate the autonomic nervous system tone, contributing to metabolic regulation.

Adropin-deficient mice develop insulin resistance and dyslipidemia on normal chow. Conversely, transgenic mice overexpressing adropin are protected against high-fat diet-induced glucose intolerance. Exogenous adropin administration (2 weeks) in diet-induced obese mice normalized fasting glucose, improved insulin tolerance, and reduced hepatic lipid accumulation, all without reducing caloric intake, distinguishing it from anorectic peptides.

Multiple clinical studies report reduced plasma adropin in coronary artery disease, heart failure, and stroke patients compared to healthy controls. Low adropin correlates with endothelial dysfunction markers (flow-mediated dilation) and inflammatory biomarkers. In cerebral ischemia mouse models, adropin given 1 hour post-stroke reduced infarct size by ~50% and improved neurological scores, supporting acute neuroprotective potential.

Plasma adropin declines with aging and is positively correlated with physical fitness and aerobic capacity. Exercise training increases adropin expression in skeletal muscle and circulating levels. This may partly explain exercise's vascular and metabolic benefits. Young blood adropin transfer experiments are being explored in the parabiosis aging model context.