2011 ADA Posters 1261-2041.indd - Diabetes

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however their effects on energy balance were elucidated by our group recently showing that kinin B1r participates in the regulation of energy balance via a mechanism that could involve the modulation of leptin sensitivity. Now, using B2 knockout mice and in vivo techniques, we present here evidence of a novel role for kinin B2r in the regulation of mitochondrial activity and adiposity. Kinin B2r defi ciency in mice (B2-/-) resulted in less fat content, higher glucose uptake in isolated muscle (C), increased lean mass and robust protection against high fat diet (HFD)-induced weight gain (A). Under HFD B2-/- exhibited improved lipid oxidation and increased energy expenditure (B). Surprisingly, B2r defi ciency led to an augment in mitochondrial activity (E), fatty acid β-oxidation related gene expression (D) and superoxide dismutase activity in muscle (F). Finally, B2r mRNA levels were signifi cantly lower in 3T3-422A differentiated adipocytes (G) and during the early days of C2C12 myoblast differentiation (H). Together, our data suggest that kinin B2 receptors participate in the regulation of energy balance via a mechanism that may involve the modulation of mitochondrial activity in muscle fi bers. Supported by: FAPESP, CNPq, CAPES 1848-P Saturated and Unsaturated Fat-Induces Tissue-Specifi c Changes in Critical Nodes of Insulin Resistance in Diet-Induced Obese (DIO) Rats SURESH K. MOHANKUMAR, PETER ZAHRADKA, DANIELLE P. HANKE, LINDA SIEMENS, CARLA TAYLOR, Winnipeg, MB, Canada The liver and peripheral tissues including skeletal muscle and adipose play a pivotal role in the pathogenesis of insulin resistance (IR) induced by high fat diets (HFD). However, the originating nodes of IR in these tissues remain poorly understood. The present study therefore investigated the tissue-specifi c changes of protein markers of IR in response to isocaloric HFD of either saturated fat (SF) or unsaturated fat (USF) in obese-prone rats. Fasting serum analysis indicated that rats fed HFD for 12 weeks were insulin resistant with marked elevation in the fasting glucose (245±22 mg/dL), insulin (45±5 µU/ml) and HOMA (27±5). Comparative analysis of gastrocnemius muscle (GM), liver (L) and epididymal adipose (EA) tissues indicated that the degree of relative phosphorylation/activation of the key nodes of IR was greater in some tissues versus others: IRS1-s 636/639 , GM>L=EA; IRS1-s 307 , GM>L=EA; AKT-s 473 , GM=EA>L; JNK, L>GM=EA; ERK, EA>GM=L, although there were no changes in the respective protein levels. These results suggest that activation of these critical nodes in response to high fat is tissue-specifi c. Next, we determined whether SF and USF differentially infl uence the critical nodes of IR. The HOMA value of SF and USF fed rats (37±4 and 19±2) indicated that SF fed rats were more insulin resistant than USF. However, there were no differences between SF and USF in the activation of the above-mentioned IR nodes. Interestingly, the animals fed USF had active tyrosine phosphorylation of AKT-t 308 , a positive regulator of insulin signaling, in GM and EA (64% and 32% increase versus SF) despite no differences in caloric intake. These results paralleled the reductions of fasting glucose, insulin and HOMA in USF fed rats (-27, -31 and -48% versus SF group), suggesting that USF sustains metabolic functions of GM and EA tissues. In summary, these data establish IRS1/AKT in muscle, JNK in liver and AKT/ERK in adipose tissue as key players in the pathogenesis of IR in response to HFD and USF delays the progression of IR via AKT. Supported by: Canola Council of Canada ADA-Funded Research & Guided Audio Tour poster OBESITY—ANIMAL CATEGORY A499 1849-P The Contribution of Enhanced Myocardial mTOR/S6K1 Activation to Impaired Insulin Signaling, Oxidative Stress and Diastolic Dysfunction in Obese db/db Mice VINCENT G. DEMARCO, JAVAD HABIBI, LAKSHMI PULAKAT, ADAM T. WHALEY- CONNELL, LIXIN MA, MELVIN R. HAYDEN, ROGER D. TILMON, C.B. KRUEGER, NA- THAN REHMER, MONA GARRO, MING YANG, JAMES R. SOWERS, Columbia, MO Obesity, the metabolic syndrome and heart failure (HF) are epidemics in the United States. Obesity related HF is characterized by decreased insulin metabolic signaling and diastolic dysfunction. We have investigated the role of mTOR/S6K1 activation in impairment of insulin metabolic signaling and diastolic relaxation in young db/db mice. The initial diastolic fi lling rate, as measured by high resolution MRI, was decreased in 12 week hyperglycemic db/db mice compared to age matched controls. There were contemporaneous increases in reactive oxygen species (ROS), increased small abnormal mitochondria, lipid accumulation and interstitial fi brosis in db/db heart. There was increased Thr 389 phosphorylation (P)/activation of S6K1, enhanced association of S6K1 with IRS-1 and Ser307 P of IRS-1. This was associated with decreased total IRS-1 and a tendency (not signifi cantly) for decreased P/activation of Akt. This is consistent with fi ndings in other tissues where S6K1 P has been associated with Ser P and associated ubiquinization/ degradation of IRS-1. A mitochondrial source of increased ROS is likely as the number of mitochondria was increased and NADPH oxidase activity was not increased in db/db heart. In summary, young db/db mice manifested diastolic dysfunction possibly due to decreased insulin metabolic signaling, increased mitochondrial generation of ROS, and interstitial fi brosis. Supported by: NIH R01-HL-63904 and VA Merit (JRS), and VA Career Development Award (AWC) 1850-P The Inhibition of Cannabionoid Receptor CB1 Increases GLUT4 Expression in Adipocytes and Adipose Tissue DANIELA T. FURUYA, ANA C. POLETTO, HELAYNE S. FREITAS, UBIRATAN F. MACHADO, São Paulo, Brazil Evidences have suggested that the endocannabinoid system is overactive in obesity, resulting in enhanced endocannabinoid levels in both circulation and visceral adipose tissue. The cannabinoid CB1 receptor is expressed in the adipose tissue besides the brain. Few studies in vitro suggest that CB1 activation increases glucose uptake in adipocytes. The objective of the present study was to investigate the CB1 receptor modulation on glucose transporter GLUT4 expression and the related mechanisms in adipocytes and adipose tissue of obese mice. For this, 3T3-L1 adipocytes were incubated in the presence of a selective agonist of CB1 receptor (1 mM ACEA) or a selective antagonist of CB1 receptor (0.1, 0.5 or 1 mM AM251) or both. After 2, 4 or 24 hours, cells were harvest to evaluate GLUT4 mRNA (Real Time PCR) and protein (Western blotting), and NFkappaB activation specifi cally in the promoter of SLC2A4 gene (EMSA) which encodes GLUT4 protein. Additionally, insulin sensitivity in vivo and GLUT4 protein from adipose tissue were assessed in monosodium glutamate–induced obese mice untreated or treated with AM251 (0.01 mg/kg body weight). Acute and chronic incubation with AM 251greatly increased GLUT4 protein content [0.1, 0.5 or 1 µM AM251 for 4 hours treatment, 309%, 313% or 357% vs C, respectively, P
Integrated Physiology/ Obesity POSTERS body fat content in dietary-induced obese rats (DIO rats). PPARg agonists, like Pioglitazone (Pio), are effi cacious drugs for the treatment of type 2 diabetes. However, a common side effect of this drug class is weight gain. Here, we investigated whether BI 10773 could attenuate Pio-induced weight gain of DIO rats after 4 weeks treatment with 10mg/kg BI 10773, 10mg/kg Pio and the combination of both (n=10 per group). Pio signifi cantly increased body weight (+6.8 %), whereas BI 10773 led to weight loss (-3.1%) compared to control animals. Animals that received BI 10773 in combination with Pio had no signifi cant increase in body weight (+1.6% vs. vehicle). As DIO rats are insulin-resistant and hyperinsulinemic we investigated the effect of the combination on metabolic parameters. Both compounds signifi cantly reduced fed plasma insulin levels (vehicle: 5.27 ± 0.7; BI 10773: 3.53 ± 0.4; Pio: 2.27 ± 0.3 ng/ml) which was further reduced (p=0.054) by the combination (BI 10773 + Pio: 1.55 ± 0.1 ng/ml). Furthermore, the combination of BI 10773 + Pio reduced plasma triglyceride levels, whereas either compound alone had no effect. As expected, BI 10773 and BI 10773 + Pio markedly increased urinary glucose excretion. After termination of the study carcass analysis was performed to assess body composition. The fat content was 147.4 + 7.8 g in the vehicle group compared to 140.7 + 7.1 g (BI 10773). Pio increased body fat content to 170 + 6.8 g but the gain in body fat was prevented by combination treatment (BI 10773 + Pio: 149.6 + 7.2 g). Our data show that BI 10773 prevented the Pio-induced body weight gain and the associated gain of body fat after 4 week treatment of DIO rats. Furthermore, BI 10773 improved hyperinsulinemia of DIO rats alone and in combination with Pio. Our data support the concept of a combination of BI 10773 with Pio for the treatment of type 2 diabetes. 1852-P Tissue-Specifi c Dysregulation of Hexose-6-Phosphate Dehydrogenase and Glucose-6-Phosphate Transporter Expression in a Mouse Model of Type 2 Diabetes YANJUN LIU, YUICHI NAKAGAWA, YING WANG, WEI WANG, JUAN ORTEGA, THEODORE C. FRIEDMAN, Los Angeles, CA, Hamamatsu, Japan Tissue-specifi c amplifi cation of glucocorticoid action through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) affects the develop ment of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates intracellular NADPH availability for 11β-HSD1 and depends on the glucose-6-phosphate transporter (G6PT). To assess whether the tissue-specifi c alterations of H6PDH and G6PT expression could contribute to local glucocorticoid action and insulin resistance in type 2 diabetes and obesity, we characterized the role of H6PDH and G6PT in pre-receptor metabolism of glucocorticoids by examining the production of the hepatic 11β-HSD1-H6PDH-G6PT system in a mouse model of type 2. We observed that increased production of hepatic H6PDH in diabetic db/db mice was paralleled by upregulation of hepatic G6PT production and elevated circulating levels of corticosterone. In contrast, pharmacological inhibition of H6PDH and G6PT expression decreased NADPH production accompanied by reduction of 11β-HSD1 in the liver and subcutaneous fat, and attenuated the phenotype of type 2 diabetes. Incubation of mouse hepatocytes with corticosterone enhanced G6PT and H6PDH production with corresponding activation of 11β-HSD1 and PEPCK. Knockdown of H6PDH by siRNA attenuated the corticosterone-induced H6PDH production in these intact cells. Addition of the G6PT inhibitor to primary hepatocytes suppressed H6PDH production. These fi ndings suggest that increased hepatic and adipose H6PDH and G6PT expression may contribute to 11β-HSD1 upregulation of local glucocorticoid action that may be related to the development of type 2 diabetes. Supported by: NIDDK SC1DK087655 1853-P TrkB Agonist Induces Body Weight Loss by Activating Satiety Centers in the Brain TIFFANY GARESKI, SARAH WILL, DAVID KUBASIAK, THADDEUS UNGER, KIMBERLY COUGHLAN, GUO FENG, YING SUN, XIANGPING LI, ARIFUL QADRI, DARRELL PANZA, SEUNG HAHM, JULI JONES, JANET PAULSEN, RUTH GIMENO, MYLENE PERREAULT, Cambridge, MA Brain-derived neurotrophin factor (BDNF) and its receptor, tropomyosinrelated kinase B (TrkB), have emerged as critical regulators of central neural circuits involved in energy homeostasis. The potential therapeutic application of TrkB activation has been demonstrated in several rodent models in which BDNF administration induced weight loss mainly through appetite suppression. In this study, we For author disclosure information, see page 785. OBESITY—HUMAN CATEGORY A500 sought to determine the biological effects of a TrkB agonist and identify its mechanism of action. Diet-induced obese (DIO) mice were injected with a potent and highly selective mouse monoclonal TrkB agonist and the effects on body weight and food intake were determined. We observed that TrkB activation induced robust and reversible weight loss accompanied by a concomitant reduction in food intake. To gain further insight into the hypophagic effect of the agonist, we studied circadian meal patterns and observed that TrkB agonism reduced the amount of food ingested per meal but did not affect meal frequency. In addition, pair-feeding experiments showed that body weight was mostly regulated by food intake. Given the high selectivity of the blood-brain-barrier, it is unknown whether the effects of this TrkB agonist on food intake are mediated through activation of TrkB receptors in the central nervous system (CNS) or periphery. To address this, we peripherally injected fl uorescently labeled TrkB agonist and detected fl uorescence in the medium eminence and the arcuate nucleus of the hypothalamus as well as the dorsal vagal complex of the hindbrain. Collectively, our studies show that TrkB agonism decreases body weight mainly by increasing satiety through direct activation of the brain satiety centers. 1854-P Weight Control Diminishes Progression of Insulin Resistance Due to Estrogen-Deprived Condition MUJALIN PRASANNARONG, KANOKWAN VICHAIWONG, VITOON SAENGSIRI- SUWAN, Bangkok, Thailand Prolonged estrogen deprivation in ovariectomized rats resulted in the phenotypic features of the metabolic syndrome including increased visceral fat accumulation, dyslipidemia, impaired glucose tolerance, and insulin resistance of skeletal muscle. Because these animals are also hyperphagic, the development of metabolic defects under estrogen-deprived condition could be confounded by excessive calorie consumption. To determine the role of calorie consumption in the development of the phenotypic characteristics of the metabolic syndrome in animal under prolonged estrogen deprivation, adult female Sprague-Dawley rats were randomly assigned to shamoperated (SHAM), ovariectomized (OVX), pair-fed ovariectomized (OVX+PF), or body weight-controlled ovariectomized (OVX+WC) groups. After a 12week experimental period, whole-body glucose tolerance, skeletal muscle insulin action, intra-abdominal fat content and serum lipid profi le were evaluated. When compared to OVX group, both pair-feeding and weight control paradigms signifi cantly reduced intra-abdominal fat accumulation by 32% and 44% (p
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2011 ADA Posters 1261-2041.indd - Diabetes

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