The nuclear receptor Rev-erbα controls circadian thermogenic plasticity

Gerhart-Hines, Zachary; Feng, Dan; Emmett, Matthew J.; Everett, Logan J.; Loro, Emanuele; Briggs, Erika R.; Bugge, Anne; Hou, Catherine; Ferrara, Christine T.; Seale, Patrick; Pryma, Daniel A.; Khurana, Tejvir S.; Lazar, Mitchell A.

doi:10.1038/nature12642

Cited by 245 publications

(258 citation statements)

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“…Rev-erb␣ Controls Enhancer RNA Expression at the Klb locus Specifically in Mouse White Adipose Tissue-Inspection of the ChIP-seq data revealed three robust Rev-erb␣ binding sites within the first intron of the Klb locus in EWAT (48) but also in liver (39) and BAT (18) (Fig. 3A, green tracks, yellow boxes).…”

Section: Resultsmentioning

confidence: 99%

“…Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13)(14)(15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT).…”

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confidence: 99%

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The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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“…A white adipocyte in vivo must adjust rates of de novo lipogenesis (DNL) and TG storage with the rate of hydrolysis of TG according to the circadian clock ( 80 ). Gerhart-Hines et al ( 81 ) recently provided clear evidence that the thermogenic program of classical BAT is under circadian control. Thus, any interpretations of adipose gene expression data should take into account the precise time of day in which the tissues are harvested.…”

Section: Additional Considerationsmentioning

confidence: 99%

Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

Wang

Scherer

Gupta

2014

Journal of Lipid Research

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greater caution must be taken in interpreting studies of adipogenesis and adipocyte metabolism.In this review, we offer a consolidated view of the wideranging approaches that can be taken to study adipose biology and discuss important considerations and pitfalls associated with each method. We divide the discussion into three sections; the fi rst section describes model systems, ways to understand where and when molecules of interest may play a role in the adipose lineage, and recent insights gained from these approaches. The second and third sections provide guidelines for the study of adipocyte biology in vivo and in cellular systems, respectively. Along the way, we highlight improved genetic and cellular models that can aid researchers interested in studying the role of their favorite protein in the adipose tissue and discuss the insights gained from each approach. IS MY FAVORITE GENE EXPRESSED IN THE ADIPOSE LINEAGE? WHERE DO I LOOK?The establishment and maintenance of adipocytes in principle involves key regulatory steps ( 3 ). First, multipotent progenitor cells must commit to the adipocyte lineage, a process referred to as preadipose cell determination. Next, in response to appropriate spatial and temporal cues, committed preadipose cells undergo adipocyte differentiation, a morphological and biochemical transition into mature adipocytes. Finally, mechanisms must exist that function to maintain the differentiated state of the mature adipocyte (adipocyte maintenance). This includes factors critical for regulating the functional properties of Abstract Adipocyte differentiation and function have become areas of intense focus in the fi eld of energy metabolism; however, understanding the role of specifi c genes in the establishment and maintenance of fat cell function can be challenging and complex. In this review, we offer practical guidelines for the study of adipocyte development and function. We discuss improved cellular and genetic systems for the study of adipose biology and highlight recent insights gained from these new approaches. -Wang, Q. A., P. E. Scherer, and R. K. Gupta. Improved methodologies for the study of adipose biology: insights gained and opportunities ahead. J. Lipid Res. 2014. 55: 605-624. Supplementary key words energy metabolism • adipogenesis • obesitySince the 1970s, fat cell differentiation of immortalized fi broblast cell lines has been an extensively studied model of cellular differentiation ( 1 ). The ability to study this process in a tissue culture dish has allowed cellular biologists and biochemists to explore general mechanisms of cell fate determination and cellular differentiation, and to isolate novel regulatory proteins and signaling cascades that initiate these processes . However, it is now clear that adipocytes represent critical regulators of nearly all aspects of energy balance. Adipose tissues exhibit high plasticity with a tremendous capacity for expansion and contraction in response to the energy demands of an organism. The alarming rise in obesity and obesity-l...

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“…The literature identifies three chronographic types or chronotype: morning, intermediate or evening (Adan, Archer, Hidalgo et al, 2012). Morning individuals prefer to go to bed and get up early, peaking before noon, and evening people, in turn, prefer to go to bed and wake up later, and perform better at the end of the day (Hines, Feng, Emmett et al, 2013;Adan et al, 2012). Since the chronotype differs in sleep-wake patterns, we consider that it is extremely important to verify the perception of parents and schools about the children's chronotype to understand academic underachievement at specific times of the school day.…”

Section: The Perceptions Of Children's Chronotype and Effective Cognimentioning

confidence: 99%

Sleep Quality And Chronotype Of Portuguese School-Aged Children

Figueiredo¹,

Gomes²,

Rocha³

et al. 2017

European Proceedings of Social and Behavioural Sciences

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Is the perception of school-aged children and parents about the children's sleep quality and chronotype consistent with their real sleep quality and effective chronotype? The research questions for this study were 1) Do children's sleep perceptions and chronotype differ from real sleep quality and chronotype? 2) Are there differences in sleep quality between genders? 3) What will be the effective quality of sleep and chronotype? The purpose of the study was to analyse the perceptions of children and parents about the children's sleep quality and chronotype and compare them with effective sleep quality and chronotype, to study sleep quality and chronotype considering gender, and to analyse the perceptions of Portuguese parents about children's sleep in a migrant context. The research method was a cross-sectional study, quantitative methodology. The data from three questionnaires were analysed with regard to the three study aims: the Pittsburgh Sleep Quality Index (PSQI) (n=1109 children), the Children's Sleep Habits Questionnaire (CSHQ) (n=883 parents), and the Children's Chronotype Questionnaire (CCTQ) (n=58 parents, Portuguese emigrants in Luxembourg). The samples were collected from 8 Portuguese schools and 2 Luxembourg schools. The PSQI showed high sleep quality, which contradicts the results for CSHQ. Children from state schools (n=538) revealed higher diurnal dysfunction levels compared to the children from private schools (n=571). Females showed best sleep latency and duration. The CSHQ presented general negative sleep quality. The CCTQ demonstrated that parents' perceptions did not fit with the effective children's chronotype. The children's perception showed a wellbalanced sleep quality but the results revealed a high incidence of sleep disturbance. There were no statistical differences for gender. Portuguese emigrant parents revealed low awareness of their children's chronotype and there was significant contrast between parents' perceptions and the real chronotype of children.

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The nuclear receptor Rev-erbα controls circadian thermogenic plasticity

Cited by 245 publications

References 30 publications

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

Sleep Quality And Chronotype Of Portuguese School-Aged Children

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