Integrating Chronophysiological and Bioinformatic Perspectives on Nesfatin-1, Circadian Feeding Rhythms, and Cortisol Regulation

Nesfatin-1, a peptide derived from nucleobindin-2, regulates feeding, stress, and sleep–wake processes. To date, the available information suggests that nesfatin-1 is involved in stress regulation and colocalises with substances that influence cortisol, but the circadian interplay between nesfatin-1 and cortisol remains poorly defined. This review integrates biological timing, tissue-specific actions of the hypothalamic–pituitary–adrenal axis, and circadian misalignment, and is supported by in silico protein-association analysis. A structured database search retained relevant studies published from January 2006 to March 2026; heterogeneity necessitated narrative synthesis. Rodent experiments support effects of central NUCB2/nesfatin-1 on feeding and HPA-axis activation. Murine corticotroph experiments report increased POMC abundance, whereas an H295R human adrenocortical carcinoma-cell study reports reduced cortisol content and stimulated release. These findings concern different experimental systems and do not demonstrate coordinated central–adrenal regulation in vivo. The network analysis identified NPY and POMC as prominent nodes within the predefined candidate network, with enrichment of feeding- and HPA-axis-related pathways. Given the biologically targeted selection of input genes, these findings are interpreted as hypothesis-generating associations rather than independent confirmation of a regulatory mechanism. Within the literature examined in this review, direct evidence characterising the 24 h temporal profile of nesfatin-1 in humans, its phase relationship with cortisol, and potential alterations during circadian misalignment was not identified. This apparent evidence gap warrants further investigation through controlled, time-resolved human studies.