Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

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Mammalian sirtuins: biological insights and disease relevance.

The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

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Central and Peripheral Circadian Clocks in Mammals

Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.

https://science.sciencemag.org/content/sci/330/6009/1349.full.pdf

Circadian Integration of Metabolism and Energetics

SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation

The circadian clock enables the anticipation of daily recurring environmental changes by presetting an organism’s physiology and behavior. Driven and synchronized by a central pacemaker in the brain, circadian output genes fine-tune a wide variety of physiological parameters in peripheral organs. However, only a subset of circadianly transcribed genes seems to be directly regulated by core clock proteins. Assuming that yet unidentified transcription factors may exist in the circadian transcriptional network, we set out to develop a novel technique, differential display of DNA-binding proteins (DDDP), which we used to screen mouse liver nuclear extracts. In addition to several established circadian transcription factors, we found DNA binding of heat-shock factor 1 (HSF1) to be highly rhythmic. HSF1 drives the expression of heat-shock proteins at the onset of the dark phase, when the animals start to be behaviorally active. Furthermore, Hsf1-deficient mice have a longer free-running period than wild-type littermates, suggesting a combined role for HSF1 in the mammalian timekeeping and cytoprotection systems. Our results also suggest that the new screening method DDDP is not limited to the identification of circadian transcription factors but can be applied to discover novel transcriptional regulators in various biological systems.

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Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor

Most living beings, including humans, must adapt to rhythmically occurring daily changes in their environment that are generated by the Earth's rotation. In the course of evolution, these organisms have acquired an internal circadian timing system that can anticipate environmental oscillations and thereby govern their rhythmic physiology in a proactive manner. In mammals, the circadian timing system coordinates virtually all physiological processes encompassing vigilance states, metabolism, endocrine functions and cardiovascular activity. Research performed during the past two decades has established that almost every cell in the body possesses its own circadian timekeeper. The resulting clock network is organized in a hierarchical manner. A master pacemaker, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, is synchronized every day to the photoperiod. In turn, the SCN determines the phase of the cellular clocks in peripheral organs through a wide variety of signalling pathways dependent on feeding cycles, body temperature rhythms, oscillating bloodborne signals and, in some organs, inputs of the peripheral nervous system. A major purpose of circadian clocks in peripheral tissues is the temporal orchestration of key metabolic processes, including food processing (metabolism and xenobiotic detoxification). Here, we review some recent findings regarding the molecular and cellular composition of the circadian timing system and discuss its implications for the temporal coordination of metabolism in health and disease. We focus primarily on metabolic disorders such as obesity and type 2 diabetes, although circadian misalignments (shiftwork or ‘social jet lag’) have also been associated with the aetiology of human malignancies.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/joim.12347

Circadian timing of metabolism in animal models and humans.

Mammalian circadian oscillators are considered to rely on transcription/translation feedback loops in clock gene expression. The major and essential loop involves the autorepression of cryptochrome (Cry1, Cry2) and period (Per1, Per2) genes. The rhythm-generating circuitry is functional in most cell types, including cultured fibroblasts. Using this system, we show that significant reduction in RNA polymerase II-dependent transcription did not abolish circadian oscillations, but surprisingly accelerated them. A similar period shortening was observed at reduced incubation temperatures in wild-type mouse fibroblasts, but not in cells lacking Per1. Our data suggest that mammalian circadian oscillators are resilient to large fluctuations in general transcription rates and temperature, and that PER1 has an important function in transcription and temperature compensation.

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Charna Dibner

Papers

The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation

Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor

Circadian timing of metabolism in animal models and humans.

Circadian gene expression is resilient to large fluctuations in overall transcription rates