The circadian clock exerts an important role in systemic homeostasis as it acts a keeper of time for the organism. The synchrony between the daily challenges imposed by the environment needs to be aligned with biological processes and with the internal circadian clock. In this review, it is provided an in-depth view of the molecular functioning of the circadian molecular clock, how this system is organized, and how central and peripheral clocks communicate with each other. In this sense, we provide an overview of the neuro-hormonal factors controlled by the central clock and how they affect peripheral tissues. We also evaluate signals released by peripheral organs and their effects in the central clock and other brain areas. Additionally, we evaluate a possible communication between peripheral tissues as a novel layer of circadian organization by reviewing recent studies in the literature. In the last section, we analyze how the circadian clock can modulate intracellular and tissue-dependent processes of metabolic organs. Taken altogether, the goal of this review is to provide a systemic and integrative view of the molecular clock function and organization with an emphasis in metabolic tissues.

Melanoma is the most lethal type of skin cancer, with increasing incidence and mortality rates worldwide. Multiple studies have demonstrated a link between cancer development/progression and circadian disruption; however, the complex role of tumor-autonomous molecular clocks remains poorly understood. With that in mind, we investigated the pathophysiological relevance of clock gene expression in metastatic melanoma. Methods: We analyzed gene expression, somatic mutation, and clinical data from 340 metastatic melanomas from The Cancer Genome Atlas, as well as gene expression data from 234 normal skin samples from Genotype-Tissue Expression. Findings were confirmed in two independent datasets. Results: In melanomas, the expression of most clock genes was remarkably reduced and displayed a disrupted pattern of co-expression compared to the normal skins, indicating a dysfunctional circadian clock. Importantly, we demonstrate that the expression of the clock gene BMAL1 positively correlates with patient overall survival and with the expression of T-cell activity and exhaustion markers in the tumor bulk. Accordingly, high BMAL1 expression in pre-treatment samples was significantly associated with clinical benefit from immune checkpoint inhibitors. The robust intratumoral T-cell infiltration/activation observed in patients with high BMAL1 expression was associated with a decreased expression of key DNA repair enzymes, and with an increased mutational/neoantigen load. Conclusions: Overall, our data corroborate previous reports regarding the impact of BMAL1 expression on the cellular DNA repair capacity and indicate that alterations in the tumor-autonomous molecular clock could influence the cellular composition of the surrounding microenvironment. Moreover, we revealed the potential of BMAL1 as a clinically relevant prognostic factor and biomarker for T-cell-based immunotherapies.

Circadian clocks are internal timekeepers enabling organisms to adapt to recurrent events in their environment – such as the succession of day and night—by controlling essential behaviors such as food intake or the sleep-wake cycle. A ubiquitous cellular clock network regulates numerous physiological processes including the endocrine system. Levels of several hormones such as melatonin, cortisol, sex hormones, thyroid stimulating hormone as well as a number of metabolic factors vary across the day, and some of them, in turn, can feedback on circadian clock rhythms. In this review, we dissect the principal ways by which hormones can regulate circadian rhythms in target tissues – as phasic drivers of physiological rhythms, as zeitgebers resetting tissue clock phase, or as tuners, affecting downstream rhythms in a more tonic fashion without affecting the core clock. These data emphasize the intricate interaction of the endocrine system and circadian rhythms and offer inroads into tissue-specific manipulation of circadian organization.