Article

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

ABSTRACT

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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    • "Thus, Rev-Erbα plays an important role in circadian and non-circadian functions. Earlier results suggest that some clock genes participate in the development of drug consumption (Abarca et al. 2002; Spanagel et al. 2005) and overeating (Turek et al. 2005). However, the role of Rev-Erbα in the regulation of compulsive or addictive feeding remains unknown. "
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    ABSTRACT: The drive to eat is regulated by two compensatory brain pathways termed as homeostatic and hedonic. Hypothalamic orexinergic (ORX) neurons regulate metabolism, feeding and reward, thus controlling physiological and hedonic appetite. Circadian regulation of feeding, metabolism and rhythmic activity of ORX cells are driven by the brain suprachiasmatic clock. How the circadian clock impacts on ORX signalling and feeding-reward rhythms is, however, unknown. Here we used mice lacking the nuclear receptor REV-ERBα, a transcription repressor and a key component of the molecular clockwork, to study food-reward behaviour. Rev-Erbα mutant mice showed highly motivated behaviours to obtain palatable food, an increase in the intake and preference for tasty diets, and in the expression of the ORX protein in the hypothalamus. Palatable food intake was inhibited in animals treated with the ORX1R antagonist. Analyzing the Orx promoter, we found Retinoic acid-related Orphan receptor Response Element binding sites for Rev-Erbα. Furthermore, Rev-Erbα dampened the activation of Orx in vitro and in vivo. Our data provide evidence for a possible repressive role of Rev-Erbα in the regulation of ORX signalling, highlighting an implication of the circadian clockwork in modulating food-reward behaviours with an important impact for the central regulation of overeating.
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    • "Given the well-established links between circadian rhythms and metabolism (DiAngelo et al., 2011; Green et al., 2008; Xu et al., 2011), we examined the role of circadian clocks in lifespan extension by DR in Drosophila. Circadian behavioral rhythms have been studied previously in the context of aging in both flies and mice, with studies showing that rhythms of rest:activity or sleep:wake break down with age (Koh et al., 2006; Turek et al., 2005). However, it is not known whether interventions that lead to life extension, such as DR, require functional circadian clocks, and if so by which mechanisms. "
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    ABSTRACT: Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass-spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging.
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    • "Transcriptome studies report that approximately 3% to 10% of genes in a given mammalian tissue are rhythmic (Cermakian and Boivin, 2009); nevertheless, the overlap between various tissues can be very small. More recently, human studies have started investigating the functions of CCGs and the external factors influencing their expression to better understand the mechanisms linking the circadian clock, sleep, and diseases such as cardiovascular disease (Takeda and Maemura, 2011; Portaluppi et al., 2012), cancer (Sahar and Sassone-Corsi, 2009; Savvidis and Koutsilieris, 2012), sleep disorders (Archer et al., 2003; Lu and Zee, 2006; Sack et al., 2007), hypertension (Scheer et al., 2009), diabetes and obesity (Laposky et al., 2008; Scheer et al., 2009), and metabolic syndrome (Turek et al., 2005; Maury et al., 2010). Knowledge about the expression of CCGs in human blood, however, remains scarce. "
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    ABSTRACT: The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings.
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