From Circadian Misalignment to Metabolic Disease: The Role of Hypothalamic-Pituitary-Adrenal Axis Hyperreactivity in Peripheral Insulin Resistance and Hepatic Steatosis - A Narrative Review

Background: Circadian rhythms are essential for maintaining metabolic homeostasis by regulating a number of metabolic processes, including energy balance, glucose metabolism, and endocrine function. Shift work, non-rational work habits, and exposure to artificial light can disrupt activity of the hypothalamic-pituitary-adrenal (HPA) axis, which may result in metabolic dysfunction. This review examines the connection between circadian disruption, HPA axis dysfunction, peripheral insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: The English language, open access literature from October 2018 to August 2026 was reviewed. PubMed, Google Scholar, Scopus and the National Center for Biotechnology Information (NCBI) were used to search for the individual keywords and Boolean combinations of circadian rhythms, HPA axis, insulin resistance, type 2 diabetes, and hepatic steatosis. Relevance of articles was selected based on their title and abstract. Data were integrated based on the biological processes and physiological pathways. Results: Preclinical and clinical data indicate that circadian misalignment causes a miscoordination between central and peripheral clocks, affects the regulation of the HPA axis, and influences cortisol. Chronic glucocorticoid elevation can lead to insulin signalling abnormalities, such as IRS-1/PI3K pathway dysfunction and decreased GLUT4 glucose uptake. At the same time, insulin resistance may be worsened by an impaired response of glucocorticoids and activation of inflammatory pathways. Disrupted clock expression in the liver impacts lipid metabolism by regulating fatty acid oxidation (PPARα) and lipogenesis (SREBP-1c) along with altered cortisol signalling. These alterations could allow for an increase in free fatty acid availability, accumulation of fat in the liver and progression of MASLD. Conclusion: Circadian disruption and HPA axis dysfunction are some of the interconnected mechanisms that can be involved in insulin resistance and MASLD. But there were a number of methodological differences among studies and the confounding effects of sleep deprivation, stress, and circadian misalignment make it difficult to interpret the results as causal. More mechanistic and longitudinal investigations are required to fully elucidate these connections and determine the effectiveness of intervention using circadian rhythm for prevention of metabolic disease.