Circadian Medicine: Chronotherapeutic Approaches to Treating Metabolic Disorders

Abstract

Circadian rhythms play a crucial role in mediating metabolic processes—including glucose homeostasis and lipid metabolism—with clock genes (CLOCK, BMAL1, PER, CRY) that are regulated by the suprachiasmatic nucleus and peripheral clocks. The modern lifestyle, which includes shift work and irregular sleep, disrupts circadian rhythms and causes circadian misalignment. This misalignment alters metabolic processes, which increases the risk of obesity, type 2 diabetes, and cardiovascular disease. Chronotherapy, which engages with biological rhythms to deliver physical or pharmacological interventions, may be an innovative method of strengthening treatment effects. Timed pharmacotherapy—such as taking metformin or statins in the evening—targets peaks in metabolic activity of circadian rhythm during dosing time and can improve glycemic control and lipid levels outside of circadian rhythms. Time-restricted feeding (TRF) protocols simultaneously expose people to food and circadian cycles to allow people to eat food primarily in temporal proximity when the circadian rhythm is engaged with food. Although TRF protocols do not enforce caloric restrictions on food intake, they have been shown to cause a reduction in body weight, improve insulin sensitivity, and glycemic control in clinical trials. Lifestyle modification is also a chronotherapeutic intervention; people can receive morning light therapy, evening exercise, and improved metabolic effects by coordinating interventions with circadian rhythms and reinforcing these interventions in their usual lifestyles. Although advances in chronotherapy are promising, the initiatives are limited due to variation of individual chronotypes or circadian rhythms, adherence issues, and the lack of large, randomized trials. Future directions should employ personalized chronotherapy utilizing new technology wearables and include circadian-aligned microbiome studies to build chronotherapeutic effect size and reduce personal variability. This review provides an overview of the underlying molecular mechanism and integrates some clinical evidence, future evidence, and unfound metabolic disorder space related to generalized chronotherapy with the hopes of revolutionizing and re-imagining metabolic disorder treatment.