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Dive into the research topics where Jennifer Jager is active.

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Featured researches published by Jennifer Jager.


Genes & Development | 2012

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

Anne Bugge; Dan Feng; Logan J. Everett; Erika R. Briggs; Shannon E. Mullican; Fenfen Wang; Jennifer Jager; Mitchell A. Lazar

The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.


American Journal of Physiology-endocrinology and Metabolism | 2010

Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans

Cédric Dray; Cyrille Debard; Jennifer Jager; Emmanuel Disse; Danièle Daviaud; Pascal Martin; Camille Attané; Estelle Wanecq; Charlotte Guigné; Frédéric Bost; Jean-François Tanti; Martine Laville; Hubert Vidal; Philippe Valet; Isabelle Castan-Laurell

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.


Science | 2015

Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock

Yuxiang Zhang; Bin Fang; Matthew J. Emmett; Manashree Damle; Zheng Sun; Dan Feng; Sean M. Armour; Jarrett R. Remsberg; Jennifer Jager; Raymond E. Soccio; David J. Steger; Mitchell A. Lazar

Multitasking around the clock Chronic disruption of our circadian rhythms—for example, through shift work—may increase the risk of metabolic disease. Zhang et al. found that a multitasking transcription factor called Rev-erb-α regulates expression of both clock and metabolic genes through distinct mechanisms. At clock genes, it binds directly to a specific DNA sequence, displacing a competing transcription factor. At metabolic genes, it interacts not with DNA but with other transcription factors that regulate metabolic gene expression in a tissue-specific manner. Science, this issue p. 1488 A transcription factor that controls both circadian rhythms and metabolism does so through different genomic mechanisms. Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type–specific transcription factors. Thus, direct competition between Rev-erbα and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbα uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.


Cell | 2014

Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo

Bin Fang; Logan J. Everett; Jennifer Jager; Erika R. Briggs; Sean M. Armour; Dan Feng; Ankur Roy; Zachary Gerhart-Hines; Zheng Sun; Mitchell A. Lazar

Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of enhancer RNAs (eRNAs) that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ.


Proceedings of the National Academy of Sciences of the United States of America | 2012

Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

Qin Yan; Ruaidhrí J. Carmody; Zhonghua Qu; Qingguo Ruan; Jennifer Jager; Shannon E. Mullican; Mitchell A. Lazar; Youhai H. Chen

Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR–Hdac3–deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR–Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.


Diabetes | 2010

Tpl2 Kinase Is Upregulated in Adipose Tissue in Obesity and May Mediate Interleukin-1β and Tumor Necrosis Factor-α Effects on Extracellular Signal–Regulated Kinase Activation and Lipolysis

Jennifer Jager; Thierry Grémeaux; Teresa González; Stéphanie Bonnafous; Cyrille Debard; Martine Laville; Hubert Vidal; Albert Tran; Philippe Gual; Yannick Le Marchand-Brustel; Mireille Cormont; Jean-François Tanti

OBJECTIVE Activation of extracellular signal–regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function. RESEARCH DESIGN AND METHODS Kinase activities were inhibited with pharmacological inhibitors or siRNA. Lipolysis was monitored through glycerol production. Gene expression in adipocytes and adipose tissue of obese mice and subjects was measured by real-time PCR. RESULTS IκB kinase-(IKK)-β inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1β and tumor necrosis factor (TNF)-α but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKβ regulated a MAP kinase kinase kinase (MAP3K) involved in ERK1/2 activation induced by inflammatory cytokines. We show that the MAP3K8 called Tpl2 was expressed in adipocytes and that IL-1β and TNF-α activated Tpl2 and regulated its expression through an IKKβ pathway. Pharmacological inhibition or silencing of Tpl2 prevented MEK/ERK1/2 activation by these cytokines but not by insulin, demonstrating its involvement in ERK1/2 activation specifically in response to inflammatory stimuli. Importantly, Tpl2 was implicated in cytokine-induced lipolysis and in insulin receptor substrate-1 serine phosphorylation. Tpl2 mRNA expression was upregulated in adipose tissue of obese mice and patients and correlated with TNF-α expression. CONCLUSIONS Tpl2 is selectively involved in inflammatory cytokine–induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity.


Molecular Endocrinology | 2014

Behavioral Changes and Dopaminergic Dysregulation in Mice Lacking the Nuclear Receptor Rev-erbα

Jennifer Jager; W. Timothy O'Brien; Jessica Manlove; Elizabeth N. Krizman; Bin Fang; Zachary Gerhart-Hines; Michael B. Robinson; Peter S. Klein; Mitchell A. Lazar

The regulation of behavior by the molecular components of the circadian clock is not well understood. Here we report that mice lacking the nuclear receptor Rev-erbα, a potent transcriptional repressor and core clock component, displayed marked hyperactivity and impaired response habituation in novel environments. In addition, Rev-erbα knockout (KO) mice were deficient in short-term, long-term, and contextual memories and also showed impairment in nest-building ability. Together, these results suggest that Rev-erbα KO mice manifest defective hippocampal function. Interestingly, the changes in novelty-induced locomotor activity of Rev-erbα KO mice were comparable at multiple times of day, potentially due to the muted amplitude of Rev-erbα oscillation in the hippocampus of wild-type mice. Hippocampal dopamine turnover was increased in Rev-erbα KO mice, due to up-regulation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine production, and pharmacologic inhibition of tyrosine hydroxylase activity partially rescued locomotor hyperactivity. These findings reveal a novel, nonredundant function for Rev-erbα that links a core component of the circadian gene-regulatory network to the control of dopaminergic and hippocampus-dependent behaviors.


Nature | 2017

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Matthew J. Emmett; Hee-Woong Lim; Jennifer Jager; Hannah J. Richter; Marine Adlanmerini; Lindsey C. Peed; Erika R. Briggs; David J. Steger; Tao Ma; Carrie A. Sims; Joseph A. Baur; Liming Pei; Kyoung-Jae Won; Patrick Seale; Zachary Gerhart-Hines; Mitchell A. Lazar

Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.


Nature Medicine | 2017

Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion

Sungguan Hong; Wenjun Zhou; Bin Fang; Wenyun Lu; Emanuele Loro; Manashree Damle; Guolian Ding; Jennifer Jager; Sisi Zhang; Yuxiang Zhang; Dan Feng; Qingwei Chu; Brian D. Dill; Henrik Molina; Tejvir S. Khurana; Joshua D. Rabinowitz; Mitchell A. Lazar; Zheng Sun

Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.


Journal of Biological Chemistry | 2016

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

Jennifer Jager; Fenfen Wang; Bin Fang; Hee-Woong Lim; Lindsey C. Peed; David J. Steger; Kyoung-Jae Won; Alexei Kharitonenkov; Andrew C. Adams; Mitchell A. Lazar

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-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue.

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Mitchell A. Lazar

University of Pennsylvania

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Bin Fang

University of Pennsylvania

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Dan Feng

University of Pennsylvania

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Zheng Sun

University of Pennsylvania

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David J. Steger

University of Pennsylvania

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Erika R. Briggs

University of Pennsylvania

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Lindsey C. Peed

University of Pennsylvania

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Manashree Damle

University of Pennsylvania

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Yuxiang Zhang

University of Pennsylvania

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