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W1855 Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Exhibit Differential Effects on Energy Expenditure and Pancreatic Islet Function
operation is dependent on improved insulin sensitivity, without the improvement in pancreatic function observed after RYGB. These differential effects of RYGB and SGx suggest means of enhancing the effectiveness of SGx by combining it with pharmacological therapies targeted at increasing EE and enhancing beta cell function.
AGA Abstracts
W1856 Neurokinin-1receptor (NK-1r) Deficiency is Associated With Reduced Weight Gain and Improved Glucose Metabolic Responses in Mice Iordanis Karagiannidis, Dimitris G. Stavrakis, Efi Kokkotou, Bakirtzi Kyriaki, Hamed Nayeb-Hashemi, Collin Bowe, James M. Bugni, Charalabos Pothoulakis Background and Aims: Substance P (SP) affects diverse physiological pathways in the periphery mainly via its high affinity neurokinin-1 receptor (NK-1R). We have recently shown, that peripheral administration of a specific NK-1R receptor antagonist to mice leads to reduced weight gain in a high fat diet mouse model and to weight loss in two different (diet-induced obesity and ob/ob) models of obesity. These effects were also associated with improved responses in obesity-associated pathophysiological conditions, such as glucose uptake, and circulating levels of insulin and leptin. Our aim was to directly assess the importance of NK-1R in diet - induced obesity using mice genetically deficient in NK-1R. Methods: NK-1R-null mice and wild type (WT) littermates were fed high fat diet for 3 weeks (n=8 mice per group). At the end of the experiment, animals were subjected to glucose tolerance tests and then sacrificed for tissue collection. Mesenteric fat was collected and used for protein and RNA isolation for western immunoblot and real-time PCR analysis, respectively. Blood levels of insulin, leptin, adiponectin, and proinflammatory cytokines were determined by ELISA. Results: NK-1 null mice demonstrated decreased wait gain (by 28%, p<0.05, n=7), during high fat feeding when compared to controls. In addition, these animals also removed glucose more readily from the circulation when challenged in comparison to WT (p<0.01 after 30 min, n=7). Interestingly at the same time point, NK-1R-KO animals also demonstrated improved glucose clearance even when compared to their pairedfed controls (which had similar weight measurements), suggesting an additional peripheral effect of SP-NK-1R-specific signaling on glucose metabolism. Compared to WT, NK-1R-null mice had reduced circulating levels of both leptin (p<0.05) and insulin (p<0.01), consistent with reduced weight of these animals. Finally, adiponectin mRNA levels were higher in fat tissue isolated from NK-1 KO animals compared to WT (p<0.05). Although the mRNA levels of TNFα and IL-6 in mesenteric fat were consistently higher in WT, compared to NK-1R-null mice, these results did not reach statistical significance. Conclusions: Our results directly demonstrate a significant role for NK-1R in obesity and obesity - associated pathophysiology. Together with our recent findings, our data also demonstrate an important role for NK-1R in adipose tissue pathophysiology, especially as it relates to the outcome of obesityassociated pathologies such as the development of insulin resistance and glucose intolerance. Supported by a Research Fellowship Award from CCFA (IK) and by NIH R01 DK047343 (CP)
W1854 Roux-en-Y Gastric Bypass Activates Brown Adipose Tissue and Increases Energy Expenditure in Obese Mice Nicholas Stylopoulos, Xiao B. Zhang, Anna-Liisa Brownell, Lee M. Kaplan Background. Recent studies suggest that Roux-en-Y gastric bypass (RYGB) induces weight loss by altering the physiologic mechanisms regulating energy balance. Using rodent models, we and others have shown that RYGB increases total and resting energy expenditure (EE). Brown adipose tissue (BAT) is a metabolic and thermoregulatory organ that has a major role in the regulation of EE in rodents, and recent data suggest that it may contribute significantly to the regulation of body weight in humans as well. Aim. To determine whether RYGB activates BAT in mice. Methods. We developed a mouse model for RYGB, which closely resembles the human procedure. We compared C57BL/6 mice with diet-induced obesity (DIO; initial body weight [BW] 50 ± 1 g) that underwent one of 3 treatments: 1) RYGB (RYGB-DIO), 2) sham operation (SO-DIO; laparotomy with intestinal transection and repair) and 3) SO with pair-feeding (PF-DIO; fed the same amount as consumed ad libitum by the RYGB-DIO group). Outcome measures included BW, body composition (by DEXA), EE (by indirect calorimetry), BAT histomorphology, and measures of BAT activation: uncoupling protein 1 (UCP1) gene and protein expression, and 18F-FDG uptake into BAT (by PET scan). Results. Ten weeks after surgery, RYGB-DIO mice weighed 38% less than SO-DIO animals (36 ± 0.9 vs. 58 ± 0.5 g; p<0.001) and had a substantially lower fat mass. After RYGB, mean fasting glucose decreased by 45% (87 ± 5.3 vs. 159 ± 11 mg/dL; p<0.001) and the overall glucose excursion after an i.p. glucose challenge decreased by 44% (1191 ± 86 vs. 2147 ± 145; p<0.05). PF-DIO mice lost 51% as much weight as their RYGB-DIO counterparts (final BW 41.2 ± 1.6 [PF-DIO] vs. 32.7 ± 2.4 g [RYGB-DIO]; p<0.001), and total oxygen consumption in RYGB-DIO was 21% greater than in SO-DIO (1196 ± 62 vs. 983 ±37 ml/h/kg0.75; p<0.05). RYGB-DIO showed distinctive changes in BAT histomorphology, including a significant reduction in lipid droplets and enhanced vascularity. RYGB-DIO mice exhibited a 1.8-fold increase in BAT UCP1 gene expression and a more diffuse and intense immunohistochemical UCP1 staining pattern. These animals also demonstrated a significant increase in 18F-FDG uptake into BAT by PET. Conclusions. RYGB increases EE in DIO mice and leads to metabolic activation of BAT. BAT activation appears to be an important mechanism by which EE is increased after surgery in this model. In view of the newly recognized importance of BAT to energy regulation in humans, understanding the physiologic and molecular mechanisms by which RYGB increases EE and activates BAT should facilitate the discovery of novel treatment options for obesity and its metabolic sequelae.
W1857 Psychophysiological Determinants of Satiation Symptoms Upendra Marreddy, Kee Seong Ng, Susan Surguy, Qasim Aziz Negative emotions are associated with increased and decreased food intake. The mechanisms for these contrasting behaviours are not known. The influence of stress & negative emotion on satiation is likely to occur through multiple physiological mechanisms. Our aim was to evaluate the affect of anxiety on gastric myoelectrical activity (GMA), autonomic nervous system (ANS) gut endocrine and stress neuroendocrine responses to a test meal. Methods: 30 healthy volunteers (26 ± 9 years, 17M & 13 F) received a 10 minute nutrient challenge (50ml/min, 1.5 kcal/ml) during either neutral or anxiogenic stimuli (electric shock threat) in a randomised order. Satiation symptoms were assessed before and after the challenge. Anxiety VAS scores, ANS, GMA (dominant power, DP, tachygastria), cortisol, gut hormones (ghrelin, glucagon-like peptide (GLP-1) and pancreatic polypeptide (PP)) responses were monitored. Results: Increased anxiety scores confirmed anxiety induction (p=<0.01). During neutral vs. anxiety emotion induction (N vs. AN), symptom scores for discomfort (1.54± 0.37 vs. 2.8±0.46 p=<0.05), fullness (5.2±0.5 vs. 6.3±0.5, p=<0.05) and belching 1.4± 0.4 vs.2.7 ±0.5, p= <0.01) were significantly higher during anxiety state. The test meal caused increase in prandial and postprandial sympathetic activity compared to baseline (cardiac sympathetic index (CSI) 1.7±0.1 vs. 2.3±0.1, & 1.7±0.1 vs. 2.4±0.1) and parasympathetic activity to decrease (cardiac vagal tone (CVT) 12.3±1.01 vs. 8.4±0.6, 12.3±1.018 vs.7.6±0.6), these changes were more pronounced after anxiety induction compared with neutral state (CSI- p=0.02 and 0.05 & CVT-p=0.001 and 0.01). GMA dominant power increase was blunted (N vs. AN, 5.05±0.9 vs-1.4±1.1, p=0.0001) with increased tachygastria (N vs. AN, 22.6±17.4 vs. 25.2±10.66 p=0.02) during the anxiety state. Anxiety state increased cortisol secretion compared with neutral (%13.71±5.5 vs. -9.06±6.19, p=0.003). The test meal increased satiation hormones, GLP-1 & PP (p=0.001&0.001), with no differences between the two emotional states. Ghrelin levels decreased after the nutrient challenge, moreover, the degree of drop was more marked during anxiety state (N vs. AN, % change -59.8 ±21.2 vs. -454.7±169.2 (p=<0.05). Ghrelin levels correlated with CVT (r=0.5, p=0.03) and cortisol responses (r=0.5 & p=0.02). Conclusion: Our results suggest that heightened meal sensations are induced by negative emotional state and result from interplay between autonomic reactivity & gastric myoelectrical responses through interaction with gut hormone responses. Further studies are now required to study the role of these psycho-physiological factors in patients with obesity.
W1855 Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Exhibit Differential Effects on Energy Expenditure and Pancreatic Islet Function Nicholas Stylopoulos, Ronit Grinbaum, Lee M. Kaplan Background. Gastrointestinal weight loss surgery (GIWLS) is the most effective treatment for severe obesity, inducing weight loss by altering physiological mechanisms of weight regulation. Although Roux-en-Y gastric bypass (RYGB) has long been the reference standard for GIWLS, sleeve gastrectomy (SGx), a procedure that creates a narrow gastric tube by removing the greater curvature of the stomach, has been shown to induce significant weight loss with lower morbidity. Understanding differences in the mechanisms of action of these 2 procedures could identify targets for enhancing the effectiveness of each of them and facilitate the development of new treatments for obesity and its metabolic complications. Aim. To determine the mechanisms of action of SGx, including those that are similar to RYGB and those unique to this procedure. Methods. We compared diet-induced obese (DIO) Osborne Mendel (OM) rats and DIO C57BL/6 mice that underwent SGx, RYGB or a sham operation (SO: laparotomy and intestinal transection with repair). Outcome measures included body weight, food intake, energy expenditure, plasma ghrelin levels and several measures of glucose homeostasis (fasting glucose, oral glucose tolerance test, HOMA-IR and HOMA-%B). Results. SGx induced a substantial and durable weight loss in DIO OM rats. Twenty-five weeks after surgery, SGx rats weighed 15.8% less than SO (569 ± 17 vs. 677 ±51 g; P<0.05). The same pattern was observed in DIO mice. During postoperative week 25, food intake was 17.5% lower in SGx rats than SO (12.5 ± 1.6 vs. 15.1 ± 0.7 g; P<0.05). There was no difference in nutrient absorption between these two groups. Surprisingly, SGx rats had only modestly lower fasting and postprandial plasma ghrelin levels than SO controls (fasting: 663 ± 61 vs. 804 ± 23 pg/mL, postprandial: 505 ± 17 vs. 639 ± 17 pg/mL; P<0.05 for both). SGx also led to substantial improvements in fasting glucose, HOMA-IR and oral glucose tolerance. Unlike RYGB, SGx did not enhance pancreatic islet function (HOMA%B) or increase energy expenditure. Total oxygen consumption was increased only after RYGB: (SO: 1245 ± 92; SGx: 1186 ± 113; RYGB: 1509 ± 155 ml/hr/kg0.75). Conclusions. SGx induces a substantial and durable weight loss in rodents without apparent toxicity. Unlike RYGB, SGx does not induce increased EE. Improved glucose metabolism after this
AGA Abstracts
S-754
AGA Abstracts
W1856 Neurokinin-1receptor (NK-1r) Deficiency is Associated With Reduced Weight Gain and Improved Glucose Metabolic Responses in Mice Iordanis Karagiannidis, Dimitris G. Stavrakis, Efi Kokkotou, Bakirtzi Kyriaki, Hamed Nayeb-Hashemi, Collin Bowe, James M. Bugni, Charalabos Pothoulakis Background and Aims: Substance P (SP) affects diverse physiological pathways in the periphery mainly via its high affinity neurokinin-1 receptor (NK-1R). We have recently shown, that peripheral administration of a specific NK-1R receptor antagonist to mice leads to reduced weight gain in a high fat diet mouse model and to weight loss in two different (diet-induced obesity and ob/ob) models of obesity. These effects were also associated with improved responses in obesity-associated pathophysiological conditions, such as glucose uptake, and circulating levels of insulin and leptin. Our aim was to directly assess the importance of NK-1R in diet - induced obesity using mice genetically deficient in NK-1R. Methods: NK-1R-null mice and wild type (WT) littermates were fed high fat diet for 3 weeks (n=8 mice per group). At the end of the experiment, animals were subjected to glucose tolerance tests and then sacrificed for tissue collection. Mesenteric fat was collected and used for protein and RNA isolation for western immunoblot and real-time PCR analysis, respectively. Blood levels of insulin, leptin, adiponectin, and proinflammatory cytokines were determined by ELISA. Results: NK-1 null mice demonstrated decreased wait gain (by 28%, p<0.05, n=7), during high fat feeding when compared to controls. In addition, these animals also removed glucose more readily from the circulation when challenged in comparison to WT (p<0.01 after 30 min, n=7). Interestingly at the same time point, NK-1R-KO animals also demonstrated improved glucose clearance even when compared to their pairedfed controls (which had similar weight measurements), suggesting an additional peripheral effect of SP-NK-1R-specific signaling on glucose metabolism. Compared to WT, NK-1R-null mice had reduced circulating levels of both leptin (p<0.05) and insulin (p<0.01), consistent with reduced weight of these animals. Finally, adiponectin mRNA levels were higher in fat tissue isolated from NK-1 KO animals compared to WT (p<0.05). Although the mRNA levels of TNFα and IL-6 in mesenteric fat were consistently higher in WT, compared to NK-1R-null mice, these results did not reach statistical significance. Conclusions: Our results directly demonstrate a significant role for NK-1R in obesity and obesity - associated pathophysiology. Together with our recent findings, our data also demonstrate an important role for NK-1R in adipose tissue pathophysiology, especially as it relates to the outcome of obesityassociated pathologies such as the development of insulin resistance and glucose intolerance. Supported by a Research Fellowship Award from CCFA (IK) and by NIH R01 DK047343 (CP)
W1854 Roux-en-Y Gastric Bypass Activates Brown Adipose Tissue and Increases Energy Expenditure in Obese Mice Nicholas Stylopoulos, Xiao B. Zhang, Anna-Liisa Brownell, Lee M. Kaplan Background. Recent studies suggest that Roux-en-Y gastric bypass (RYGB) induces weight loss by altering the physiologic mechanisms regulating energy balance. Using rodent models, we and others have shown that RYGB increases total and resting energy expenditure (EE). Brown adipose tissue (BAT) is a metabolic and thermoregulatory organ that has a major role in the regulation of EE in rodents, and recent data suggest that it may contribute significantly to the regulation of body weight in humans as well. Aim. To determine whether RYGB activates BAT in mice. Methods. We developed a mouse model for RYGB, which closely resembles the human procedure. We compared C57BL/6 mice with diet-induced obesity (DIO; initial body weight [BW] 50 ± 1 g) that underwent one of 3 treatments: 1) RYGB (RYGB-DIO), 2) sham operation (SO-DIO; laparotomy with intestinal transection and repair) and 3) SO with pair-feeding (PF-DIO; fed the same amount as consumed ad libitum by the RYGB-DIO group). Outcome measures included BW, body composition (by DEXA), EE (by indirect calorimetry), BAT histomorphology, and measures of BAT activation: uncoupling protein 1 (UCP1) gene and protein expression, and 18F-FDG uptake into BAT (by PET scan). Results. Ten weeks after surgery, RYGB-DIO mice weighed 38% less than SO-DIO animals (36 ± 0.9 vs. 58 ± 0.5 g; p<0.001) and had a substantially lower fat mass. After RYGB, mean fasting glucose decreased by 45% (87 ± 5.3 vs. 159 ± 11 mg/dL; p<0.001) and the overall glucose excursion after an i.p. glucose challenge decreased by 44% (1191 ± 86 vs. 2147 ± 145; p<0.05). PF-DIO mice lost 51% as much weight as their RYGB-DIO counterparts (final BW 41.2 ± 1.6 [PF-DIO] vs. 32.7 ± 2.4 g [RYGB-DIO]; p<0.001), and total oxygen consumption in RYGB-DIO was 21% greater than in SO-DIO (1196 ± 62 vs. 983 ±37 ml/h/kg0.75; p<0.05). RYGB-DIO showed distinctive changes in BAT histomorphology, including a significant reduction in lipid droplets and enhanced vascularity. RYGB-DIO mice exhibited a 1.8-fold increase in BAT UCP1 gene expression and a more diffuse and intense immunohistochemical UCP1 staining pattern. These animals also demonstrated a significant increase in 18F-FDG uptake into BAT by PET. Conclusions. RYGB increases EE in DIO mice and leads to metabolic activation of BAT. BAT activation appears to be an important mechanism by which EE is increased after surgery in this model. In view of the newly recognized importance of BAT to energy regulation in humans, understanding the physiologic and molecular mechanisms by which RYGB increases EE and activates BAT should facilitate the discovery of novel treatment options for obesity and its metabolic sequelae.
W1857 Psychophysiological Determinants of Satiation Symptoms Upendra Marreddy, Kee Seong Ng, Susan Surguy, Qasim Aziz Negative emotions are associated with increased and decreased food intake. The mechanisms for these contrasting behaviours are not known. The influence of stress & negative emotion on satiation is likely to occur through multiple physiological mechanisms. Our aim was to evaluate the affect of anxiety on gastric myoelectrical activity (GMA), autonomic nervous system (ANS) gut endocrine and stress neuroendocrine responses to a test meal. Methods: 30 healthy volunteers (26 ± 9 years, 17M & 13 F) received a 10 minute nutrient challenge (50ml/min, 1.5 kcal/ml) during either neutral or anxiogenic stimuli (electric shock threat) in a randomised order. Satiation symptoms were assessed before and after the challenge. Anxiety VAS scores, ANS, GMA (dominant power, DP, tachygastria), cortisol, gut hormones (ghrelin, glucagon-like peptide (GLP-1) and pancreatic polypeptide (PP)) responses were monitored. Results: Increased anxiety scores confirmed anxiety induction (p=<0.01). During neutral vs. anxiety emotion induction (N vs. AN), symptom scores for discomfort (1.54± 0.37 vs. 2.8±0.46 p=<0.05), fullness (5.2±0.5 vs. 6.3±0.5, p=<0.05) and belching 1.4± 0.4 vs.2.7 ±0.5, p= <0.01) were significantly higher during anxiety state. The test meal caused increase in prandial and postprandial sympathetic activity compared to baseline (cardiac sympathetic index (CSI) 1.7±0.1 vs. 2.3±0.1, & 1.7±0.1 vs. 2.4±0.1) and parasympathetic activity to decrease (cardiac vagal tone (CVT) 12.3±1.01 vs. 8.4±0.6, 12.3±1.018 vs.7.6±0.6), these changes were more pronounced after anxiety induction compared with neutral state (CSI- p=0.02 and 0.05 & CVT-p=0.001 and 0.01). GMA dominant power increase was blunted (N vs. AN, 5.05±0.9 vs-1.4±1.1, p=0.0001) with increased tachygastria (N vs. AN, 22.6±17.4 vs. 25.2±10.66 p=0.02) during the anxiety state. Anxiety state increased cortisol secretion compared with neutral (%13.71±5.5 vs. -9.06±6.19, p=0.003). The test meal increased satiation hormones, GLP-1 & PP (p=0.001&0.001), with no differences between the two emotional states. Ghrelin levels decreased after the nutrient challenge, moreover, the degree of drop was more marked during anxiety state (N vs. AN, % change -59.8 ±21.2 vs. -454.7±169.2 (p=<0.05). Ghrelin levels correlated with CVT (r=0.5, p=0.03) and cortisol responses (r=0.5 & p=0.02). Conclusion: Our results suggest that heightened meal sensations are induced by negative emotional state and result from interplay between autonomic reactivity & gastric myoelectrical responses through interaction with gut hormone responses. Further studies are now required to study the role of these psycho-physiological factors in patients with obesity.
W1855 Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Exhibit Differential Effects on Energy Expenditure and Pancreatic Islet Function Nicholas Stylopoulos, Ronit Grinbaum, Lee M. Kaplan Background. Gastrointestinal weight loss surgery (GIWLS) is the most effective treatment for severe obesity, inducing weight loss by altering physiological mechanisms of weight regulation. Although Roux-en-Y gastric bypass (RYGB) has long been the reference standard for GIWLS, sleeve gastrectomy (SGx), a procedure that creates a narrow gastric tube by removing the greater curvature of the stomach, has been shown to induce significant weight loss with lower morbidity. Understanding differences in the mechanisms of action of these 2 procedures could identify targets for enhancing the effectiveness of each of them and facilitate the development of new treatments for obesity and its metabolic complications. Aim. To determine the mechanisms of action of SGx, including those that are similar to RYGB and those unique to this procedure. Methods. We compared diet-induced obese (DIO) Osborne Mendel (OM) rats and DIO C57BL/6 mice that underwent SGx, RYGB or a sham operation (SO: laparotomy and intestinal transection with repair). Outcome measures included body weight, food intake, energy expenditure, plasma ghrelin levels and several measures of glucose homeostasis (fasting glucose, oral glucose tolerance test, HOMA-IR and HOMA-%B). Results. SGx induced a substantial and durable weight loss in DIO OM rats. Twenty-five weeks after surgery, SGx rats weighed 15.8% less than SO (569 ± 17 vs. 677 ±51 g; P<0.05). The same pattern was observed in DIO mice. During postoperative week 25, food intake was 17.5% lower in SGx rats than SO (12.5 ± 1.6 vs. 15.1 ± 0.7 g; P<0.05). There was no difference in nutrient absorption between these two groups. Surprisingly, SGx rats had only modestly lower fasting and postprandial plasma ghrelin levels than SO controls (fasting: 663 ± 61 vs. 804 ± 23 pg/mL, postprandial: 505 ± 17 vs. 639 ± 17 pg/mL; P<0.05 for both). SGx also led to substantial improvements in fasting glucose, HOMA-IR and oral glucose tolerance. Unlike RYGB, SGx did not enhance pancreatic islet function (HOMA%B) or increase energy expenditure. Total oxygen consumption was increased only after RYGB: (SO: 1245 ± 92; SGx: 1186 ± 113; RYGB: 1509 ± 155 ml/hr/kg0.75). Conclusions. SGx induces a substantial and durable weight loss in rodents without apparent toxicity. Unlike RYGB, SGx does not induce increased EE. Improved glucose metabolism after this
AGA Abstracts
S-754