Adropin: A cardio-metabolic hormone in the periphery, a neurohormone in the brain?

Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (ENHO) gene. First described as a feeding-responsive, liver-secreted peptide ("hepatokine") involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.