Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043-1045

Department of Neurology, Northwestern University, Evanston, IL 60208, USA.
Science (Impact Factor: 33.61). 06/2005; 308(5724):1043-5. DOI: 10.1126/science.1108750
Source: PubMed


The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

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Available from: Ganka Ivanova, Oct 01, 2015
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    • "Circadian clocks emerged during evolution to enable uni-and multicellular organisms to efficiently anticipate and adapt to environmental changes during day-night cycles (Bass, 2012; Bass and Takahashi, 2010). Circadian rhythms affect almost all aspects of physiology, including daily activity patterns (Bunger et al., 2000), mood regulation (Chung et al., 2014), cell cycle control (Matsuo et al., 2003), metabolism (Turek et al., 2005), and immune responses (Curtis et al., 2014; Scheiermann et al., 2013). In mammals, the central clock is located in the suprachiasmatic nucleus of the brain. "
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    ABSTRACT: Circadian rhythms regulate many aspects of physiology, ranging from sleep-wake cycles and metabolic parameters to susceptibility to infection. The molecular clock, with transcription factor BMAL1 at its core, controls both central and cell-intrinsic circadian rhythms. Using a circadian reporter, we observed dynamic regulation of clock activity in lymphocytes. However, its disruption upon conditional Bmal1 ablation did not alter T- or B-cell differentiation or function. Although the magnitude of interleukin 2 (IL-2) production was affected by the time of bacterial infection, it was independent of cell-intrinsic expression of BMAL1. The circadian gating of the IL-2 response was preserved in Bmal1-deficient T cells, despite a slight reduction in cytokine production in a competitive setting. Our results suggest that, contrary to the prevailing view, the adaptive immune response is not affected by the cell-intrinsic clock but is likely influenced by cell-extrinsic circadian cues operating across multiple cell types. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(9). DOI:10.1016/j.celrep.2015.04.058 · 8.36 Impact Factor
    • "–/– cells (Guo et al., 2012) but could also reflect differences in feeding patterns of Bmal1 –/– and Clock m/m mice, which eat a similar amount of food to that eaten by wild-type mice but consume a higher proportion of calories during the day (Turek et al., 2005; Lamia et al., 2008 "
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    ABSTRACT: Circadian clocks optimize the timing of physiological processes in synchrony with daily recurring and therefore predictable changes in the environment. Until the late 1990s, circadian clocks were thought to exist only in the central nervous systems of animals; elegant studies in cultured fibroblasts and using genetically encoded reporters in Drosophila melanogaster and in mice showed that clocks are ubiquitous and cell autonomous. These findings inspired investigations of the advantages construed by enabling each organ to independently adjust its function to the time of day. Studies of rhythmic gene expression in several organs suggested that peripheral organ clocks might play an important role in optimizing metabolic physiology by synchronizing tissue-intrinsic metabolic processes to cycles of nutrient availability and energy requirements. The effects of clock disruption in liver, pancreas, muscle, and adipose tissues support that hypothesis. Adipose tissues coordinate energy storage and utilization and modulate behavior and the physiology of other organs by secreting hormones known as "adipokines." Due to behavior- and environment-driven diurnal variations in supply and demand for chemical and thermal energy, adipose tissues might represent an important peripheral location for coordinating circadian energy balance (intake, storage, and utilization) over the whole organism. Given the complexity of adipose cell types and depots, the sensitivity of adipose tissue biology to age and diet composition, and the plethora of known and yet-to-be-discovered adipokines and lipokines, we have just begun to scratch the surface of understanding the role of circadian clocks in adipose tissues. © 2015 The Author(s).
    Journal of Biological Rhythms 04/2015; 30(5). DOI:10.1177/0748730415581234 · 2.77 Impact Factor
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    • "ds to several metabolic abnormali - ties . Homozygous Clock mutant mice show an attenuated daily rhythm of food intake , as well as hyperphagia and increased adi - posity . In addition , they develop metabolic impairments such as hyperglycemia , dislipidemia , hypoinsulinemia , hepatic steatosis and reduced gluconeogenesis ( Rudic et al . , 2004 ; Turek et al . , 2005 ) . On the other hand , the Clock mutation in melatonin - proficient mice does not lead to obesity , but does impair glucose tolerance ( Kennaway et al . , 2007 ) . Furthermore , the Clock gene mutation results in dampened oscillations of hepatic glycogen and glycogen syn - thase 2 ( Gys2 ) , the rate limiting enzyme of glycogenesis , e"
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    ABSTRACT: Most aspects of energy metabolism display clear variations during day and night. This daily rhythmicity of metabolic functions, including hormone release, is governed by a circadian system that consists of the master clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and many secondary clocks in the brain and peripheral organs. The SCN control peripheral timing via the autonomic and neuroendocrine system, as well as via behavioural outputs. The sleep-wake cycle, the feeding/fasting rhythm and most hormonal rhythms, including that of leptin, ghrelin and glucocorticoids, usually show an opposite phase (relative to the light-dark cycle) in diurnal and nocturnal species. By contrast, the SCN clock is most active at the same astronomical times in these two categories of mammals. Moreover, in both species, pineal melatonin is secreted only at night. In this review we describe the current knowledge on the regulation of glucose and lipid metabolism by central and peripheral clock mechanisms. Most experimental knowledge comes from studies in nocturnal laboratory rodents. Nevertheless, we will also mention some relevant findings in diurnal mammals, including humans. It will become clear that as a consequence of the tight connections between the circadian clock system and energy metabolism, circadian clock impairments (e.g., mutations or knock-out of clock genes) and circadian clock misalignments (such as during shift work and chronic jet-lag) have an adverse effect on energy metabolism, that may trigger or enhancing obese and diabetic symptoms. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 02/2015; DOI:10.1016/j.mce.2015.01.024 · 4.41 Impact Factor
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