2011 ADA Posters 1261-2041.indd - Diabetes

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1687-P Free Fatty Acid-Induced Hepatic Insulin Resistance Is Mediated by Endoplasmic Reticulum Stress CRISTINA DIRLEA, SANDRA PEREIRA, ADRIA GIACCA, Toronto, ON, Canada Insulin resistance is a common feature of obesity and is primarily caused by an increased release of free fatty acids (FFA) and altered release of adipokines from the expanded adipose tissue. FFA-induced insulin resistance has different mechanisms depending on the tissue type and although previous work in our lab has shown activation of c-Jun-N-terminal kinase (JNK) in the liver upon short-term lipid infusion, whether JNK is causal in FFA-induced insulin resistance is unknown. One potential mechanism of JNK activation is as a result of endoplasmic reticulum (ER) stress. Therefore, the present study investigates the causal roles of ER stress and JNK in FFA-induced insulin resistance. Wistar rats were infused intravenously for 7 hours with saline or Intralipid plus heparin to elevate plasma FFA with or without an ER stress inhibitor (4-phenylbutyrate (4-PBA)) or a JNK inhibitor (SP600125). Insulin-induced suppression of endogenous glucose production during hyperinsulinemic-euglycemic clamp was measured using tracer methods. 4-PBA co-infusion prevented FFA-induced hepatic insulin resistance (P
Integrated Physiology/ Obesity POSTERS In this study, we identify the histone demethylase plant homeodomain (PHD) fi nger 2 (phf2) as an important regulator of both glycolytic and lipogenic gene expression acting as an upstream regulator of ChREBP activity. In cultured mouse hepatocytes, using chromatin immunoprecipitation (ChIP) analysis, we show that phf2 is recruited to the ChoRE containing region of both glycolytic and lipogenic gene promoters (including LPK and FAS) in response to glucose and insulin stimulation. Then, phf2 specifi cally demethylates di-methylated lysine 9 on histone H3 (H3K9Me2) allowing the recruitment of ChREBP to these promoters to increase fatty acid synthesis. In the opposite, phf2 silencing results in increased H3K9Me2 methylation at these promoters, resulting in decreased of ChREBP occupancy and inhibition of fatty acid synthesis. Finally, in liver of fed diabetic db/db mice, high phf2 activity at these glycolytic and lipogenic gene promoters is associated with decreased H3K9Me2 methylation and increased ChREBP transcriptional activity, correlating with the development of hepatic steatosis. Our fi ndings suggest that inhibition of phf2 activity in liver may be benefi cial for treating hepatic steatosis in state of obesity and type 2 diabetes. Supported by: Agence Nationale de la recherhe (ANR-09-JCJC-0057-01) and by the FRM 1692-P Prenatal Protein Defi ciency Alters Circadian Rhythms in Core Clock Oscillator Protein Expression in the Offspring ARMAND V. CENTANNI, DIANA C. ALBARADO, GREGORY M. SUTTON, Baton Rouge, LA The mechanisms linking intrauterine growth retardation (IUGR) with adulthood obesity and diabetes are unknown. Previous studies performed in our lab have demonstrated an altered circadian phenotype in 8 wk old male C57Bl/6J mice subjected to protein malnutrition (undernourished offspring, UO) in utero coupled with altered glucose homeostasis. Gene expression of the nuclear receptor, Rev-erbα, a component of the circadian clock mechanism in liver was dramatically reduced and out of phase in UO at 8 wk of age compared to control offspring (CO). Rev-erbα repressed genes involved in circadian regulation (Bmal1 and Per2) were increased in UO mice. Surprisingly, protein expression of Rev-erbα in UO liver did not oscillate and was expressed at similar levels at circadian time points (CT) 1200 and 2400 (noon and midnight) suggesting gene expression and protein translation are misaligned compared to CO. Phosphorylation of glycogen synthase kinase- 3β and protein kinase B, two second messenger signaling molecules that play a role both directly (GSK3β) and indirectly (PKB) in Rev-erbα regulation. We now demonstrate that phosphorylation at the GSKβ site on Rev-erbα is dramatically reduced in UO liver, suggesting altered transcription and regulation. These data suggest potentially cell surface signaling, perhaps through insulin may play a role in impaired clock controlled processes in UO mice. We conclude that UO mice exhibit a metabolic disorder involving abnormal circadian patterns of gene and protein expression. Altered Reverbα expression and function may be a key factor in metabolic dysregulation associated with IUGR. <strong>ADA</strong>-Funded Research 1693-P Pyruvate Carboxylase, a Novel Therapeutic Target for Type 2 <strong>Diabetes</strong> NAOKI KUMASHIRO, SARA A. BEDDOW, IOANA FAT, SACHIN K. MAJUMDAR, FITSUM GUEBRE-EGZIABHER, JENNIFER L. CHRISTIANSON, PRASAD MANCHEM, BRETT P. MONIA, SANJAY BHANOT, GERALD I. SHULMAN, VARMAN T. SAMUEL, New Haven, CT, Carlsbad, CA Fasting hyperglycemia in T2D is due to increased gluconeogenesis, a process for which the enzymatic regulation is poorly understood. We recently observed an association between fasting hyperglycemia and expression of pyruvate carboxylase (PC) but not PEPCK and G6Pase in several rodent models and thus, hypothesized that PC is an excellent therapeutic target for T2D. To test this, we used antisense oligonucleotides (ASO’s) to decrease PC expression in normal SD rats fed a regular chow, high-fat fed (HFF) SD rats and Zucker Diabetic Fatty (ZDF) rats. ASO’s specifi cally decrease target expression in liver and adipose but not other tissues (e.g. pancreas). PC ASO treatment decreased PC expression by ∼90%. In regular chow fed rats, this reduced plasma glucose concentrations in both the fasted [Cont: 109±1 vs. PC: 103±1, (P
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2011 ADA Posters 1261-2041.indd - Diabetes

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