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OR09-1 Neonatal Exendin-4 Normalizes Epigenetic Modifications at the Proximal Promoter of PGC1-Α in IUGR Rat Liver

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OR09-1 Neonatal Exendin-4 Normalizes Epigenetic Modifications at the Proximal Promoter of PGC1-Α in IUGR Rat Liver ENDO 2010 Abstract OR09-1 Neonatal Exendin-4 Normalizes Epigenetic Modifications at the Proximal Promoter of PGC1-α in IUGR Rat Liver. SE Pinney MD1, Y Han MD1 and RA Simmons MD1. 1Children's Hosp Philadelphia, Univ Pennsylvania Sch of Med Philadelphia, PA. Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adults. IUGR impairs hepatic mitochondrial function in prediabetic IUGR animals. PGC1-a is a transcriptional coactivator and metabolic regulator that promotes mitochondrial biogenesis and is critical for normal mitochondrial function. Expression is decreased in IUGR liver. Exendin-4 (Ex4), a long-acting agonist of the glucose dependent insulinotropic hormone (GLP-1), improves mitochondria function, normalizes hepatic insulin resistance, and prevents diabetes in the IUGR rat. The objectives were to determine if Ex4 normalizes PGC1- α expression; and whether changes in expression are linked to epigenetic modifications at the PGC1- α promoter. IUGR newborn pups were treated with a 6-day course (day 1-6) of Ex4 and liver was harvested for analyses at 8 weeks of age. Gene expression was measured by quantitative (q)-PCR. Histone modifications were evaluated by chromatin immunoprecipitation assays and q-PCR. PGC1- α gene expression was decreased in adult IUGR animals compared to control by 80% (p=0.017) and Ex4 treatment normalized PGC1-expression to levels equivalent to controls (p=0.36). Similarly, mitochondrial DNA and protein content were significantly reduced in IUGR liver (62±4.2% of controls, p=0.012) and neonatal Ex4 treatment normalized mitochondria content (102±4.6% of controls, p=0.45). In IUGR liver, H3 acetylation and H3K4 trimethylation at the proximal promoter of PGC1- α were markedly reduced (16±0.09% and 19±0.05% of controls, respectively (p<0.05). p300 is a transcriptional co-activator with histone acetyl transferase activity (HAT) and has been shown to increase acetylation at a number of metabolic genes. In IUGR liver, p300 binding at the proximal promoter of PGC1- α was 12±0.04% of control (p<0.01). Neonatal Ex4 treatment of the IUGR pups increased acetylation of H3 by 80% (p=0.029), increased trimethylation of H3K4 by 80% (p=0.045) and p300 binding by 95% (p=0.038) at the PGC1- α promoter. We speculate that Ex4 normalizes hepatic mitochondrial function by increasing HAT activity (via recruitment of p300), which in turn mediates epigenetic modifications at PGC1- α thereby increasing expression of PGC1- α. Sources of Research Support: NIH Grants DK55704, DK062965 awarded to RAS. Nothing to Disclose: SEP, YH, RAS Endocrine Reviews, Supplement 1, June 2010, 31[3]: S809 ENDO 2010 Abstract OR09-2 Key Role of AMP-Activated Protein Kinase in Pancreatic Beta Cell Glucose-Sensing and Whole Body Glucose Homeostasis. K Piipari1, C Beall2, H Al-Qassab1, MA Smith1, D Carling3, B Viollet4, MLJ Ashford2 and DJ Withers1. 1Rayne Inst, Univ Coll London London, UK ; 2BioMed Res Inst, Univ of Dundee Dundee, UK ; 3MRC Clin Scis Ctr, Imperial Coll London London, UK and 4Inst Cochin, Univ Paris Descartes Paris, France. AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status and regulator of organismal energy homeostasis. AMPK activates catabolic pathways that generate ATP and switches off ATP-consuming processes through acute phosphorylation of metabolic enzymes and long-term alterations in gene expression. Pancreatic beta cells require metabolism of glucose and ATP production for glucose-stimulated insulin secretion (GSIS). While this link suggests a potential role for AMPK signaling in beta cell function, the precise involvement of AMPK in insulin secretion from beta cells is at present unclear and controversial. To investigate the role of AMPK catalytic isoforms in glucose homeostasis, we generated RIPCreα2KO mice lacking the AMPKα2 catalytic subunit in beta cells and in a population of hypothalamic neurons and α1KORIPCreα2KO mice, which were additionally globally deleted for the AMPKα1 catalytic subunit. RIPCreα2KO mice displayed normal food intake and body weight. However, they developed age-dependent glucose intolerance and defective in vivo GSIS. α1KORIPCreα2KO mice displayed a more severe and earlier onset of impaired glucose homeostasis and abnormal in vivo GSIS. Beta cell mass was normal in both mouse lines. In islets isolated from RIPCreα2KO and α1KORIPCreα2KO mice GSIS was defective. Furthermore, islets displayed increased basal insulin secretion in response to low glucose. Perforated patch electrophysiological studies demonstrated that in contrast to control cells, beta cells from RIPCreα2KO and α1KORIPCreα2KO mice failed to hyperpolarize when glucose concentration was decreased. Further investigation of the mechanisms underlying this abnormality showed normal expression of Glut2 and glucokinase, normal KATP channel function and normal mitochondrial density. In contrast, expression levels of uncoupling protein 2 (UCP2) were significantly reduced. Furthermore, exposure of wild type beta cells to genipin, a UCP2 inhibitor, although not altering beta cell electrical characteristics in the presence of 10 mmol/l glucose, prevented the hyperpolarization normally associated with hypoglycaemic challenge. Together, these results suggest a key role for beta cell AMPK in sensing low glucose levels and suppressing insulin secretion via a UCP2 dependent mechanism. AMPK is also required for GSIS involving mechanisms that remain to be fully elucidated. Sources of Research Support: MRC. Nothing to Disclose: KP, CB, HA-Q, MAS, DC, BV, MLJA, DJW Endocrine Reviews, Supplement 1, June 2010, 31[3]: S810 ENDO 2010 Abstract OR09-3 FoxO1 and Notch1 Interact To Promote Hepatic Gluconeogenesis. UB Pajvani MD, PhD1, VT Samuel MD, PhD2, GI Shulman MD, PhD2 and D Accili MD1. 1Columbia Univ New York, NY and 2Yale Univ New Haven, CT. The role of the Notch family of transmembrane receptors in differentiation is well-established, but Notch signaling in developed liver and regulation by metabolic stimuli is unknown. We have previously demonstrated that FoxO1, one of the primary transcriptional regulators of hepatic gluconeogenesis, promotes corepressor clearance from the Notch effector RBP-Jκ, allowing activation of the differentiation program in many cell types. We hypothesized that similar interactions regulate FoxO1-dependent metabolic functions. Of the four Notch receptors, Notch1 and 2 are the predominant isoforms in liver, and both receptors as well as its ligands are metabolically regulated, leading to increased expression of targets of Notch signaling in the fed state. To identify the role of Notch1 signaling in developed liver, we modestly overexpressed its intracellular domain (N1-IC), which signals constitutively in a ligand-independent manner, in primary hepatocytes or in whole liver. In both models, N1-IC transduction increased expression of gluconeogenic genes (G6Pase and PEPCK) resulting in augmented hepatocyte glucose output and elevated serum glucose and insulin levels, indicative of hepatic insulin resistance. Conversely, treatment of either isolated primary hepatocytes or mice with Notch inhibitors improved hepatic insulin sensitivity through inhibition of gluconeogenic gene expression. We created FoxO1-Notch1 double-heterozygous (F/N) mice in order to circumvent the embryonic lethality of homozygous mutation of either FoxO1 or Notch1. F/N mice develop normally and despite unchanged body composition as compared to FoxO1 heterozygote littermate controls, upon challenge with high-fat diet feeding, demonstrate improved glucose tolerance and insulin sensitivity. In hyperinsulinemic-euglycemic clamps, F/N mice show decreased hepatic glucose output and increased muscle glucose uptake as compared to FoxO1 heterozygote mice, implying metabolic synergy between these two pathways. Finally, we created a liver-specific knockout of the Notch effector, RBP-Jκ – these mice are similarly protected from high-fat diet-induced hepatic insulin resistance; further, mice with liver-specific deletions of both FoxO1 and RBP-Jκ, similar to the effects seen in the F/N mice, are more insulin sensitive than liver-specific FoxO1 mice. In summary, we identify Notch signaling as a regulator of systemic insulin sensitivity and a novel molecular target to modify FoxO1 function in diabetic patients. Sources of Research Support: Endocrine Fellows Foundation Grant to UBP; NIH 1F32DK084583-01 to UBP. Nothing to Disclose: UBP, VTS, GIS, DA Endocrine Reviews, Supplement 1, June 2010, 31[3]: S811 ENDO 2010 Abstract OR09-4 The Control of Hepatic Glucose Production by Coactivator-p300. Ling He MD, PhD1, Karuna Naik PhD2, Aniket Sidhaye MD1, Sally Radovick MD1 and Fredric E. Wondisford MD1. 1Johns Hopkins Univ Sch of Med Baltimore, MD and 2Univ of Chicago Chicago, IL. The cardinal feature of diabetes mellitus (DM) is fasting hyperglycemia due to inappropriate hepatic glucose production (HGP). Glucagon increases hepatic gluconeogenesis via a cAMP-PKA signaling pathway leading to the formation of an activated CREB-p300/CBP-CRTC2 complex and increased transcription of gluconeogenic enzyme genes; insulin disassembles the complex and suppresses hepatic gluconeogenesis. We assessed the relative importance of CREB coactivators in mediating HGP in mice by depleting co-activators individually or in combination using adenoviral shRNAs and found that depletion of either CBP or p300 reduced blood glucose levels during a prolonged fast and knockdown of both CBP and p300 led to a decrease in blood
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