Honors & Awards

  • K99/R00 Pathway to Independence Award, NIA/NIH (2012-2017)

Professional Education

  • Postdoctoral Fellow, Harvard Medical School, Dana-Farber Cancer Institute, Cell Biology (2010)
  • Doctor of Philosophy, Johns Hopkins University (2007)

Stanford Advisors


All Publications

  • mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C., Goodell, M. A., Rando, T. A. 2014; 510 (7505): 393-396


    A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term GAlert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into GAlert and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-GAlert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into GAlert possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into GAlert functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.

    View details for DOI 10.1038/nature13255

    View details for PubMedID 24870234

  • mTORC1 controls the adaptive transition of quiescent stem cells from G(0) to G(Alert) NATURE Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C., Goodell, M. A., Rando, T. A. 2014; 510 (7505): 393-?
  • Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature Kraus, D., Yang, Q., Kong, D., Banks, A. S., Zhang, L., Rodgers, J. T., Pirinen, E., Pulinilkunnil, T. C., Gong, F., Wang, Y., Cen, Y., Sauve, A. A., Asara, J. M., Peroni, O. D., Monia, B. P., Bhanot, S., Alhonen, L., Puigserver, P., Kahn, B. B. 2014; 508 (7495): 258-262


    In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

    View details for DOI 10.1038/nature13198

    View details for PubMedID 24717514

  • Cdc2-Like Kinase 2 Suppresses Hepatic Fatty Acid Oxidation and Ketogenesis Through Disruption of the PGC-1α and MED1 Complex. Diabetes Tabata, M., Rodgers, J. T., Hall, J. A., Lee, Y., Jedrychowski, M. P., Gygi, S. P., Puigserver, P. 2014; 63 (5): 1519-32


    Hepatic ketogenesis plays an important role in catabolism of fatty acids during fasting along with dietary lipid overload, but the mechanisms regulating this process remain poorly understood. Here, we show that Cdc2-like kinase 2 (Clk2) suppresses fatty acid oxidation and ketone body production during diet-induced obesity. In lean mice, hepatic Clk2 protein is very low during fasting and strongly increased during feeding; however, in diet-induced obese mice, Clk2 protein remains elevated through both fed and fasted states. Liver-specific Clk2 knockout mice fed a high-fat diet exhibit increased fasting levels of blood ketone bodies, reduced respiratory exchange ratio, and increased gene expression of fatty acid oxidation and ketogenic pathways. This effect of Clk2 is cell-autonomous, because manipulation of Clk2 in hepatocytes controls genes and rates of fatty acid utilization. Clk2 phosphorylation of peroxisome proliferator-activated receptor γ coactivator (PGC-1α) disrupts its interaction with Mediator subunit 1, which leads to a suppression of PGC-1α activation of peroxisome proliferator-activated receptor α target genes in fatty acid oxidation and ketogenesis. These data demonstrate the importance of Clk2 in the regulation of fatty acid metabolism in vivo and suggest that inhibition of hepatic Clk2 could provide new therapies in the treatment of fatty liver disease.

    View details for DOI 10.2337/db13-1304

    View details for PubMedID 24458359

  • USP7 attenuates hepatic gluconeogenesis through modulation of FoxO1 gene promoter occupancy. Molecular endocrinology (Baltimore, Md.) Hall, J. A., Tabata, M., Rodgers, J. T., Puigserver, P. 2014: me20131420


    Hepatic forkhead protein FoxO1 is a key component of systemic glucose homeostasis via its ability to regulate the transcription of rate-limiting enzymes in gluconeogenesis. Important in the regulation of FoxO1 transcriptional activity are the modifying/de-modifying enzymes that lead to posttranslational modification. Here, we demonstrate the functional interaction and regulation of FoxO1 by USP7, a deubiquitinating enzyme. We show that USP7-mediated mono-deubiquitination of FoxO1 results in suppression of FoxO1 transcriptional activity through decreased FoxO1 occupancy on the promoters of gluconeogenic genes. Knockdown of USP7 in primary hepatocytes leads to increased expression of FoxO1-target gluconeogenic genes and elevated glucose production. Consistent with this, USP7 gain-of-function suppresses the fasting/cAMP-induced activation of gluconeogenic genes in hepatocyte cells and in mouse liver, resulting in decreased hepatic glucose production. Notably, we show that the effects of USP7 on hepatic glucose metabolism depend on FoxO1. Together, these results place FoxO1 under the intimate regulation of deubiquitination and glucose metabolic control with important implication in diseases such as diabetes.

    View details for DOI 10.1210/me.2013-1420

    View details for PubMedID 24694308

  • Sprouting a new take on stem cell aging EMBO JOURNAL Rodgers, J. T., Rando, T. A. 2012; 31 (21): 4103-4105

    View details for DOI 10.1038/emboj.2012.281

    View details for Web of Science ID 000310724300004

    View details for PubMedID 23042560

  • Clk2 and B56 beta Mediate Insulin-Regulated Assembly of the PP2A Phosphatase Holoenzyme Complex on Akt MOLECULAR CELL Rodgers, J. T., Vogel, R. O., Puigserver, P. 2011; 41 (4): 471-479


    Akt mediates important cellular decisions involved in growth, survival, and metabolism. The mechanisms by which Akt is phosphorylated and activated in response to growth factors or insulin have been extensively studied, but the molecular regulatory components and dynamics of Akt attenuation are poorly understood. Here we show that a downstream target of insulin-induced Akt activation, Clk2, triggers Akt dephosphorylation through the PP2A phosphatase complex. Clk2 phosphorylates the PP2A regulatory subunit B56? (PPP2R5B, B'?), which is a critical regulatory step in the assembly of the PP2A holoenzyme complex on Akt leading to dephosphorylation of both S473 and T308 Akt sites. Since Akt plays a pivotal role in cellular signaling, these results have important implications for our understanding of Akt regulation in many biological processes.

    View details for DOI 10.1016/j.molcel.2011.02.007

    View details for Web of Science ID 000287773300011

    View details for PubMedID 21329884

  • Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP GENES & DEVELOPMENT Walker, A. K., Yang, F., Jiang, K., Ji, J., Watts, J. L., Purushotham, A., Boss, O., Hirsch, M. L., Ribich, S., Smith, J. J., Israelian, K., Westphal, C. H., Rodgers, J. T., Shioda, T., Elson, S. L., Mulligan, P., Najafi-Shoushtari, H., Black, J. C., Thakur, J. K., Kadyk, L. C., Whetstine, J. R., Mostoslavsky, R., Puigserver, P., Li, X., Dyson, N. J., Hart, A. C., Naar, A. M. 2010; 24 (13): 1403-1417


    The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.

    View details for DOI 10.1101/gad.1901210

    View details for Web of Science ID 000279405000009

    View details for PubMedID 20595232

  • Cdc2-like Kinase 2 Is an Insulin-Regulated Suppressor of Hepatic Gluconeogenesis CELL METABOLISM Rodgers, J. T., Haas, W., Gygi, S. P., Puigserver, P. 2010; 11 (1): 23-34


    Dynamic regulation of insulin signaling and metabolic gene expression is critical to nutrient homeostasis; dysregulation of these pathways is widely implicated in insulin resistance and other disease states. Though the metabolic effects of insulin are well established, the components linking insulin signal transduction to a metabolic response are not as well understood. Here, we show that Cdc2-like kinase 2 (Clk2) is an insulin-regulated suppressor of hepatic gluconeogenesis and glucose output. Clk2 protein levels and kinase activity are induced as part of the hepatic refeeding response by the insulin/Akt pathway. Clk2 directly phosphorylates the SR domain on PGC-1alpha, resulting in repression of gluconeogenic gene expression and hepatic glucose output. In addition, Clk2 is downregulated in db/db mice, and reintroduction of Clk2 largely corrects glycemia. Thus, we have identified a role for and regulation of the Clk2 kinase as a component of hepatic insulin signaling and glucose metabolism.

    View details for DOI 10.1016/j.cmet.2009.11.006

    View details for Web of Science ID 000273617000007

    View details for PubMedID 20074525

  • Foxo1 integrates insulin signaling with mitochondrial function in the liver NATURE MEDICINE Cheng, Z., Guo, S., Copps, K., Dong, X., Kollipara, R., Rodgers, J. T., DePinho, R. A., Puigserver, P., White, M. F. 2009; 15 (11): 1307-U105


    Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Ppargc-1alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.

    View details for DOI 10.1038/nm.2049

    View details for Web of Science ID 000271543700019

    View details for PubMedID 19838201

  • Insulin resistance: beta-arrestin development CELL RESEARCH Rodgers, J. T., Puigserver, P. 2009; 19 (3): 275-276

    View details for DOI 10.1038/cr.2009.22

    View details for Web of Science ID 000265700000001

    View details for PubMedID 19252509

  • A PGC-1 alpha-O-GlcNAc Transferase Complex Regulates FoxO Transcription Factor Activity in Response to Glucose JOURNAL OF BIOLOGICAL CHEMISTRY Housley, M. P., Udeshi, N. D., Rodgers, J. T., Shabanowitz, J., Puigserver, P., Hunt, D. F., Hart, G. W. 2009; 284 (8): 5148-5157


    Metabolic and stress response gene regulation is crucial for the survival of an organism to a changing environment. Three key molecules that sense nutrients and broadly affect gene expression are the FoxO transcription factors, the transcriptional co-activator PGC-1alpha, and the dynamic post-translational modification, O-linked beta-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1alpha, including O-GlcNAc, and describe a novel mechanism for how PGC-1alpha co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1alpha binds to O-GlcNAc transferase and targets the enzyme to FoxOs, resulting in their increased GlcNAcylation and increased transcriptional activity. Furthermore, glucose-enhanced activation of FoxO1 occurs via this PGC-1alpha-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1alpha can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase GlcNAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.

    View details for DOI 10.1074/jbc.M808890200

    View details for Web of Science ID 000263416600045

    View details for PubMedID 19103600

  • O-GlcNAc regulates FoxO activation in response to glucose JOURNAL OF BIOLOGICAL CHEMISTRY Housley, M. P., Rodgers, J. T., Udeshi, N. D., Kelly, T. J., Shabanowitz, J., Hunt, D. F., Puigserver, P., Hart, G. W. 2008; 283 (24): 16283-16292


    FoxO proteins are key transcriptional regulators of nutrient homeostasis and stress response. The transcription factor FoxO1 activates expression of gluconeogenic, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and also activates the expression of the oxidative stress response enzymes catalase and manganese superoxide dismutase. Hormonal and stress-dependent regulation of FoxO1 via acetylation, ubiquitination, and phosphorylation, are well established, but FoxOs have not been studied in the context of the glucose-derived O-linked beta-N-acetylglucosamine (O-GlcNAc) modification. Here we show that O-GlcNAc on hepatic FoxO1 is increased in diabetes. Furthermore, O-GlcNAc regulates FoxO1 activation in response to glucose, resulting in the paradoxically increased expression of gluconeogenic genes while concomitantly inducing expression of genes encoding enzymes that detoxify reactive oxygen species. GlcNAcylation of FoxO provides a new mechanism for direct nutrient control of transcription to regulate metabolism and stress response through control of FoxO1 activity.

    View details for DOI 10.1074/jbc.M802240200

    View details for Web of Science ID 000256497100004

    View details for PubMedID 18420577

  • Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways FEBS LETTERS Rodgers, J. T., Lerin, C., Gerhart-Hines, Z., Puigserver, P. 2008; 582 (1): 46-53


    Energy homeostasis in mammals is achieved through tight regulation of tissue-specific metabolic pathways that become dysregulated in metabolic diseases including diabetes and obesity. At the molecular level, main nutrient and hormonal signaling pathways impinge on expression of genes encoding for metabolic enzymes. Among the major components of this transcriptional circuitry are the PGC-1 alpha transcriptional complexes. An important regulatory mechanism of this complex is through acetylation and SIRT1-mediated lysine de-acetylation under low nutrient conditions. Activation of SIRT1 can mimic several metabolic aspects of calorie restriction that target selective nutrient utilization and mitochondrial oxidative function to regulate energy balance. Thus, understanding the PGC-1 alpha and SIRT1 pathways might have important implications for comprehending metabolic and age-associated diseases.

    View details for DOI 10.1016/j.febslet.2007.11.034

    View details for Web of Science ID 000257023100008

    View details for PubMedID 18036349

  • mTOR controls mitochondrial oxidative function through a YY1-PGC-1 alpha transcriptional complex NATURE Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., Puigserver, P. 2007; 450 (7170): 736-U12


    Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.

    View details for DOI 10.1038/nature06322

    View details for Web of Science ID 000251209700057

    View details for PubMedID 18046414

  • Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rodgers, J. T., Puigserver, P. 2007; 104 (31): 12861-12866


    In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1alpha plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1alpha. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1alpha. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.

    View details for DOI 10.1073/pnas.0702509104

    View details for Web of Science ID 000248603900049

    View details for PubMedID 17646659

  • SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis EMBO JOURNAL Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., Puigserver, P., Sinclair, D. A., Tsai, L. 2007; 26 (13): 3169-3179


    A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

    View details for DOI 10.1038/sj.emboj.7601758

    View details for Web of Science ID 000248038500012

    View details for PubMedID 17581637

  • Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1 alpha EMBO JOURNAL Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S., Mostoslavsky, R., Alt, F. W., Wu, Z., Puigserver, P. 2007; 26 (7): 1913-1923


    In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.

    View details for DOI 10.1038/sj.emboj.7601633

    View details for Web of Science ID 000245465800015

    View details for PubMedID 17347648

  • Receptor feasts on sugar and cholesterol NATURE MEDICINE Rodgers, J. T., Puigserver, P. 2007; 13 (2): 128-129

    View details for Web of Science ID 000244031700017

    View details for PubMedID 17290267

  • Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1 alpha PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cha, S., Rodgers, J. T., Puigserver, P., Chohnan, S., Lane, M. D. 2006; 103 (42): 15410-15415


    Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The "malonyl-CoA signal" is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (< or =2 h) up-regulated the expression (in skeletal muscle) of the beta-adrenergic signaling molecules, i.e., norepinephrine, beta3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator gamma coactivator 1alpha (PGC-1alpha) and estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone-cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1alpha in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.

    View details for DOI 10.1073/pnas.0607334103

    View details for Web of Science ID 000241476200026

    View details for PubMedID 17030788

  • Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction JOURNAL OF BIOLOGICAL CHEMISTRY Qin, W., Yang, T., Ho, L., Zhao, Z., Wang, J., Chen, L., Zhao, W., Thiyagarajan, M., MacGrogan, D., Rodgers, J. T., Puigserver, P., Sadoshima, J., Deng, H., Pedrini, S., Gandy, S., Sauve, A. A., Pasinetti, G. M. 2006; 281 (31): 21745-21754


    Nicotinamide adenine dinucleotide (NAD)+-dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD+-dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that alpha-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated alpha-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.

    View details for DOI 10.1074/jbc.M602909200

    View details for Web of Science ID 000239387100020

    View details for PubMedID 16751189

  • GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1 alpha CELL METABOLISM Lerin, C., Rodgers, J. T., Kalume, D. E., Kim, S., Pandey, A., Puigserver, P. 2006; 3 (6): 429-438


    Hormonal and nutrient regulation of hepatic gluconeogenesis mainly occurs through modulation of the transcriptional coactivator PGC-1alpha. The identity of endogenous proteins and their enzymatic activities that regulate the functions and form part of PGC-1alpha complex are unknown. Here, we show that PGC-1alpha is in a multiprotein complex containing the acetyltransferase GCN5. PGC-1alpha is directly acetylated by GCN5 resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci. Adenoviral-mediated expression of GCN5 in cultured hepatocytes and in mouse liver largely represses activation of gluconeogenic enzymes and decreases hepatic glucose production. Thus, we have identified the endogenous PGC-1alpha protein complex and provided the molecular mechanism by which PGC-1alpha acetylation by GCN5 turns off the transcriptional and biological function of this metabolic coactivator. GCN5 might be a pharmacological target to regulate the activity of PGC-1alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is dysregulated.

    View details for DOI 10.1016/j.cmet.2006.04.013

    View details for Web of Science ID 000238199600007

    View details for PubMedID 16753578

  • Certainly can't live without this: SIRT6 CELL METABOLISM Rodgers, J. T., Puigserver, P. 2006; 3 (2): 77-78


    Cellular metabolic rates might regulate aging by impinging on genomic stability through the DNA repair pathways. A new study published in Cell (Mostoslavsky et al., 2006) reports that deficiency in one of the mammalian Sir2 homologs, SIRT6, results in genome instability through the DNA base excision repair pathway and leads to aging-associated degenerative phenotypes.

    View details for DOI 10.1016/j.cmet.2006.01.009

    View details for Web of Science ID 000235439700001

    View details for PubMedID 16459306

  • Foxa2, a novel transcriptional regulator of insulin sensitivity NATURE MEDICINE Puigserver, P., Rodgers, J. T. 2006; 12 (1): 38-39

    View details for Web of Science ID 000234419000033

    View details for PubMedID 16397559

  • Nutrient control of glucose homeostasis through a complex of PGC-1 alpha and SIRT1 NATURE Rodgers, J. T., Lerin, C., HAAS, W., Gygi, S. P., Spiegelman, B. M., Puigserver, P. 2005; 434 (7029): 113-118


    Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

    View details for DOI 10.1038/nature03354

    View details for Web of Science ID 000227334600054

    View details for PubMedID 15744310

  • Discrimination among individual Watson-Crick base pairs at the termini of single DNA hairpin molecules NUCLEIC ACIDS RESEARCH Vercoutere, W. A., Winters-Hilt, S., DeGuzman, V. S., Deamer, D., Ridino, S. E., Rodgers, J. T., Olsen, H. E., Marziali, A., Akeson, M. 2003; 31 (4): 1311-1318


    Nanoscale alpha-hemolysin pores can be used to analyze individual DNA or RNA molecules. Serial examination of hundreds to thousands of molecules per minute is possible using ionic current impedance as the measured property. In a recent report, we showed that a nanopore device coupled with machine learning algorithms could automatically discriminate among the four combinations of Watson-Crick base pairs and their orientations at the ends of individual DNA hairpin molecules. Here we use kinetic analysis to demonstrate that ionic current signatures caused by these hairpin molecules depend on the number of hydrogen bonds within the terminal base pair, stacking between the terminal base pair and its nearest neighbor, and 5' versus 3' orientation of the terminal bases independent of their nearest neighbors. This report constitutes evidence that single Watson-Crick base pairs can be identified within individual unmodified DNA hairpin molecules based on their dynamic behavior in a nanoscale pore.

    View details for DOI 10.1093/nar/gkg218

    View details for Web of Science ID 000181115100029

    View details for PubMedID 12582251

  • Use of biotin-labeled nucleic acids for protein purification and agarose-based chemiluminescent electromobility shift assays ANALYTICAL BIOCHEMISTRY Rodgers, J. T., Patel, P., Hennes, J. L., Bolognia, S. L., Mascotti, D. P. 2000; 277 (2): 254-259


    We have employed biotin-labeled RNA to serve two functions. In one, the biotin tethers the RNA to streptavidin-agarose beads, creating an affinity resin for protein purification. In the other, the biotin functions as a label for use in a modified chemiluminescent electromobility shift assay (EMSA), a technique used to detect the formation of protein-RNA complexes. The EMSA that we describe avoids the use not only of radioactivity but also of neurotoxic acrylamide by using agarose as the gel matrix in which the free nucleic acid is separated from protein-nucleic acid complexes. After separation of free from complexed RNA in agarose, the RNA is electroblotted to positively charged nylon. The biotin-labeled RNA is readily bound by a streptavidin-alkaline phosphatase conjugate, allowing for very sensitive chemiluminescent detection ( approximately 0.1-1.0 fmol limit). Using our system, we were able to purify both known iron-responsive proteins (IRPs) from rat liver and assess their binding affinity to RNA containing the iron-responsive element (IRE) using the same batch of biotinylated RNA. We show data indicating that agarose is especially useful for cases when large complexes are formed, although smaller complexes are even better resolved.

    View details for Web of Science ID 000085230700013

    View details for PubMedID 10625515

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