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Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity
Abstracts / Appetite 57S (2011) S1–S49
transgenic drosophila can be a valuable model for future pathogenesis and therapeutic studies. Supported by NIH. doi:10.1016/j.appet.2011.05.214 Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity C.M. LO 1 , M. GEORGIEVSKY 1 , S.C. WOODS 2 , P. TSO 1 1 Department of Pathology and Laboratory Medicine, Universtiy of Cincinnati, Cincinnati, USA 2 Department of Psychiatry, University of Cincinnati, Cincinnati, USA Background and aims: Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. We hypothesized that mice lacking the CCK gene and fed a 20% butter diet fat would have alterations of fat metabolism. Methods: We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK knockout (CCK-KO) mice in an automated measurement system. Additionally, intestinal fat absorption and energy expenditure were determined by utilizing a non-invasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively. Results: After consumption of a high-fat diet for 10 weeks, CCK-KO mice exhibited reduced body weight gain and body fat mass, and enlarged adipocytes, despite normal food intake. CCK-KO mice had defective fat absorption, especially for long-chain saturated fatty acids, but pancreatic triglyceride lipase (PTL) did not play a critical role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type (WT) mice, and CCK-KO mice displayed greater carbohydrate oxidation during high-fat feeding. Conclusion: We conclude that CCK is involved in regulating metabolic rate and is important for lipid absorption and the control of body weight during high-fat feeding. Supported by: NIH NIDDK. doi:10.1016/j.appet.2011.05.215 Central GLP-1 receptor signaling directly controls brown adipose tissue thermogenesis S.H. LOCKIE 6,1 , N. CHAUDHARY 1 , K. HEPPNER 1 , D. SMILEY 2 , D. MORGAN 3 , D. DRUCKER 4 , J. CHABENNE 2 , K. RAHMOUNI 3 , F. ROHNER-JEANRENAUD 5 , B.J. OLDFIELD 6 , M.H. TSCHOEP 1 , D. PEREZ-TILVE 1 1 University of Cincinnati, Cincinnati, USA 2 University of Indiana, Bloomington, USA 3 University of Iowa, Iowa City, USA 4 Samuel Lunenfeld Research Institute, Toronto, Canada 5 University of Geneva, Geneva, Switzerland 6 Monash University, Clayton, Australia Proglucagon gives rise to a number of biologically active peptides by site specific posttranslational processing. GLP-1, oxyntomodulin (OXM) and glucagon have all been implicated in controlling energy balance. OXM binds to both the GLP-1 and glucagon receptors (GLP-1R and GCGR) and little is known about which receptor mediates its effects. Chronic administration of GLP1, OXM or a soluble, anionic glucagon full agonist (IUB94) into the lateral ventricle via osmotic minipump significantly decreased body weight. Acute ICV administration of all peptides significantly increased both activity of the sympathetic nerves innervating the interscapular brown adipose tissue (BAT) and BAT temperature. The effect of OXM on BAT thermogenesis persisted with chronic ICV infusion in WT mice, an effect absent in GLP-1R KO mice, showing the effect is dependent on GLP-1R signalling. Chronic ICV infusion of OXM did not affect peripheral insulin sensitivity measured by euglycemic–hyperinsulinemic clamp. These data demonstrate a role for central GLP-1R and GCGR signalling in controlling BAT thermogenesis. Our results suggest that the increase in non-shivering thermogenesis may contribute to the anti-obesity benefits of therapies based on GLP-1R and GCGR agonism. doi:10.1016/j.appet.2011.05.216
S27
Sucralose preferring and avoiding rats perceive the taste of sucralose as qualitatively different G.C. LONEY, G.D. BLONDE, L.A. ECKEL, A.C. SPECTOR Program in Neuroscience, Department of Psychology Florida State University, Tallahassee, USA Sucralose, an artificial sweetener, elicits a robust bimodal preference response in rats. About 70% of rats tested in a two-bottle preference test display clear avoidance responses to concentrations ≥0.01 g/L (sucralose avoiders; SAs), while the remaining rats display preferences over water at these same concentrations (sucralose preferrers; SPs). It is unclear, however, whether the functional basis underlying these different phenotypes relates to the qualitative perceptual properties of sucralose or only its evaluation by so called “reward” circuits. In humans, some artificial sweeteners elicit bitter side tastes depending on concentration and some bind with members of the T2R taste receptors that are activated by bitter tasting ligands. To test the hypothesis that SAs and SPs differ with respect to their perception of a quinine-like taste quality of sucralose, we trained SPs and SAs in a two-response operant taste discrimination task to lick one response spout if the sampled stimulus was sucrose and a different response spout if it was quinine hydrochloride. We then assessed which response spout the rats licked when given nonreinforced test trials with sucralose. SPs treated sucralose as if it were perceived as more sucrose-like, and thus less quinine-like, compared to SAs, with this difference peaking at the 16.0 g/L concentration (91.7% ± 8.2 & 51.8% ± 15.0, respectively; P < 0.05). We conclude that SAs and SPs perceive the taste of sucralose differently, which likely contributes to the difference in their preference phenotype. doi:10.1016/j.appet.2011.05.217 Differential neuronal encoding in the nucleus accumbens is associated with behavioral indices of conditioned taste aversion learning A.L. LORIAUX, J.D. ROITMAN, M.F. ROITMAN Department of Psychology, University of Illinois at Chicago, Chicago, USA Our lab has found that, in a Pavlovian conditioned taste aversion (CTA) paradigm, responses of NAc neurons encode the change in hedonic value of a taste stimulus. Here, we tested whether the NAc could track the hedonic value of cues associated with taste stimuli gradually made aversive through CTA learning. Rats (n = 10) were trained to press one of two levers for an intra-oral infusion of either orange- or grape-flavored sucrose. Different cues (tones) preceded each lever presentation. During conditioning, only one cue-lever-flavor combination was presented on each day, followed by an injection of either LiCl or saline. After conditioning (6–10 sessions), rats were tested in a session in which both cue-leverflavor combinations were presented pseudo-randomly. During all sessions the electrophysiological activity of single NAc neurons was recorded. While operant responding for both flavors was equally high at the beginning of the conditioning sessions, responding for the LiCl-paired flavor significantly decreased by the end of training in 9 of the 10 rats. Likewise, during the test session rats avoided responding on the LiCl-paired lever and preferentially responded for the saline-paired flavor. Initial electrophysiological results suggest the NAc differentially responds to the two cues after conditioning and during the test session - where the saline-paired cue evoked significantly more activity relative to the LiCl-paired cue. This differential activity may direct behavior towards ‘safe’ flavors and away from ‘harmful’ ones. Supported by: UIC Chancellor’s Supplemental Graduate Research Fellowship (ALL) DA025634 (MFR). doi:10.1016/j.appet.2011.05.218
transgenic drosophila can be a valuable model for future pathogenesis and therapeutic studies. Supported by NIH. doi:10.1016/j.appet.2011.05.214 Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity C.M. LO 1 , M. GEORGIEVSKY 1 , S.C. WOODS 2 , P. TSO 1 1 Department of Pathology and Laboratory Medicine, Universtiy of Cincinnati, Cincinnati, USA 2 Department of Psychiatry, University of Cincinnati, Cincinnati, USA Background and aims: Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. We hypothesized that mice lacking the CCK gene and fed a 20% butter diet fat would have alterations of fat metabolism. Methods: We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK knockout (CCK-KO) mice in an automated measurement system. Additionally, intestinal fat absorption and energy expenditure were determined by utilizing a non-invasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively. Results: After consumption of a high-fat diet for 10 weeks, CCK-KO mice exhibited reduced body weight gain and body fat mass, and enlarged adipocytes, despite normal food intake. CCK-KO mice had defective fat absorption, especially for long-chain saturated fatty acids, but pancreatic triglyceride lipase (PTL) did not play a critical role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type (WT) mice, and CCK-KO mice displayed greater carbohydrate oxidation during high-fat feeding. Conclusion: We conclude that CCK is involved in regulating metabolic rate and is important for lipid absorption and the control of body weight during high-fat feeding. Supported by: NIH NIDDK. doi:10.1016/j.appet.2011.05.215 Central GLP-1 receptor signaling directly controls brown adipose tissue thermogenesis S.H. LOCKIE 6,1 , N. CHAUDHARY 1 , K. HEPPNER 1 , D. SMILEY 2 , D. MORGAN 3 , D. DRUCKER 4 , J. CHABENNE 2 , K. RAHMOUNI 3 , F. ROHNER-JEANRENAUD 5 , B.J. OLDFIELD 6 , M.H. TSCHOEP 1 , D. PEREZ-TILVE 1 1 University of Cincinnati, Cincinnati, USA 2 University of Indiana, Bloomington, USA 3 University of Iowa, Iowa City, USA 4 Samuel Lunenfeld Research Institute, Toronto, Canada 5 University of Geneva, Geneva, Switzerland 6 Monash University, Clayton, Australia Proglucagon gives rise to a number of biologically active peptides by site specific posttranslational processing. GLP-1, oxyntomodulin (OXM) and glucagon have all been implicated in controlling energy balance. OXM binds to both the GLP-1 and glucagon receptors (GLP-1R and GCGR) and little is known about which receptor mediates its effects. Chronic administration of GLP1, OXM or a soluble, anionic glucagon full agonist (IUB94) into the lateral ventricle via osmotic minipump significantly decreased body weight. Acute ICV administration of all peptides significantly increased both activity of the sympathetic nerves innervating the interscapular brown adipose tissue (BAT) and BAT temperature. The effect of OXM on BAT thermogenesis persisted with chronic ICV infusion in WT mice, an effect absent in GLP-1R KO mice, showing the effect is dependent on GLP-1R signalling. Chronic ICV infusion of OXM did not affect peripheral insulin sensitivity measured by euglycemic–hyperinsulinemic clamp. These data demonstrate a role for central GLP-1R and GCGR signalling in controlling BAT thermogenesis. Our results suggest that the increase in non-shivering thermogenesis may contribute to the anti-obesity benefits of therapies based on GLP-1R and GCGR agonism. doi:10.1016/j.appet.2011.05.216
S27
Sucralose preferring and avoiding rats perceive the taste of sucralose as qualitatively different G.C. LONEY, G.D. BLONDE, L.A. ECKEL, A.C. SPECTOR Program in Neuroscience, Department of Psychology Florida State University, Tallahassee, USA Sucralose, an artificial sweetener, elicits a robust bimodal preference response in rats. About 70% of rats tested in a two-bottle preference test display clear avoidance responses to concentrations ≥0.01 g/L (sucralose avoiders; SAs), while the remaining rats display preferences over water at these same concentrations (sucralose preferrers; SPs). It is unclear, however, whether the functional basis underlying these different phenotypes relates to the qualitative perceptual properties of sucralose or only its evaluation by so called “reward” circuits. In humans, some artificial sweeteners elicit bitter side tastes depending on concentration and some bind with members of the T2R taste receptors that are activated by bitter tasting ligands. To test the hypothesis that SAs and SPs differ with respect to their perception of a quinine-like taste quality of sucralose, we trained SPs and SAs in a two-response operant taste discrimination task to lick one response spout if the sampled stimulus was sucrose and a different response spout if it was quinine hydrochloride. We then assessed which response spout the rats licked when given nonreinforced test trials with sucralose. SPs treated sucralose as if it were perceived as more sucrose-like, and thus less quinine-like, compared to SAs, with this difference peaking at the 16.0 g/L concentration (91.7% ± 8.2 & 51.8% ± 15.0, respectively; P < 0.05). We conclude that SAs and SPs perceive the taste of sucralose differently, which likely contributes to the difference in their preference phenotype. doi:10.1016/j.appet.2011.05.217 Differential neuronal encoding in the nucleus accumbens is associated with behavioral indices of conditioned taste aversion learning A.L. LORIAUX, J.D. ROITMAN, M.F. ROITMAN Department of Psychology, University of Illinois at Chicago, Chicago, USA Our lab has found that, in a Pavlovian conditioned taste aversion (CTA) paradigm, responses of NAc neurons encode the change in hedonic value of a taste stimulus. Here, we tested whether the NAc could track the hedonic value of cues associated with taste stimuli gradually made aversive through CTA learning. Rats (n = 10) were trained to press one of two levers for an intra-oral infusion of either orange- or grape-flavored sucrose. Different cues (tones) preceded each lever presentation. During conditioning, only one cue-lever-flavor combination was presented on each day, followed by an injection of either LiCl or saline. After conditioning (6–10 sessions), rats were tested in a session in which both cue-leverflavor combinations were presented pseudo-randomly. During all sessions the electrophysiological activity of single NAc neurons was recorded. While operant responding for both flavors was equally high at the beginning of the conditioning sessions, responding for the LiCl-paired flavor significantly decreased by the end of training in 9 of the 10 rats. Likewise, during the test session rats avoided responding on the LiCl-paired lever and preferentially responded for the saline-paired flavor. Initial electrophysiological results suggest the NAc differentially responds to the two cues after conditioning and during the test session - where the saline-paired cue evoked significantly more activity relative to the LiCl-paired cue. This differential activity may direct behavior towards ‘safe’ flavors and away from ‘harmful’ ones. Supported by: UIC Chancellor’s Supplemental Graduate Research Fellowship (ALL) DA025634 (MFR). doi:10.1016/j.appet.2011.05.218