Adropin is a peptide hormone, which plays a role in energy homeostasis and controls glucose and fatty acid metabolism. Its levels correlate with changes in carbohydratelipid metabolism, metabolic diseases, central nervous system function, endothelial function and cardiovascular disease. Both metabolic pathways and adropin are regulated by the circadian clocks. Here, we review the roles of the autonomic nervous system and circadian rhythms in regulating metabolic pathways and energy homeostasis. The beneficial effects of chronotherapy in various systems are discussed. We suggest a potential role for adropin as a mediator of the metabolic system-autonomic nervous system axis. We discuss the possibility of establishing an individualized adropin and circadian rhythm-based platform for implementing chronotherapy, and variability signatures for improving the efficacy of adropin-based therapies are discussed. K E Y W O R D S adropin, autonomic nervous system, chronobiology, metabolic syndrome 1 | INTRODUCTION Metabolic syndrome (MetS) is a cluster of metabolic and cardiovascular complications, which increase the risk of cardiovascular diseases (CVD) and type 2 diabetes (T2D). 1 The pathogenesis of MetS involves multiple factors, including the autonomic nervous system (ANS) and the circadian rhythm. 2 Recently, MetS was also shown to increase the risk and mortality of cancer, 3 with which it shares many risk factors including age, genetic factors, obesity, physical inactivity, unhealthy diet, alcohol, smoking, endocrine disruptors exposure and air pollution. Recent studies have suggested that several peptide hormones play important roles in the modulation of systemic metabolism and energy homeostasis. Adropin is a product of the energy homeostasis associated (Enho) gene and a peptide hormone that plays a role in the regulation of energy homeostasis and controls glucose and fatty acid metabolism. It was originally described as a secreted peptide, with