fat-preference-a-novel-model-of-eating-behavior-in-rats

Fat Preference: A Novel Model of Eating Behavior in Rats

Obesity is a growing problem in the United States of America, with more than a third of the population classified as obese. One factor contributing to ...

University of Texas Medical Branch

university of texas medical branch

Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.

Local gene knockdown in the brain using viral-mediated RNA interference.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin- and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser845. Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.

The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance.

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.

Leptin receptor signaling in midbrain dopamine neurons regulates feeding.

&Mu; &#x963F;&#x7247;&#x53D7;&#x4F53; (&#x94C1;&#x9053;&#x90E8;) agonism &#x8BF1;&#x5BFC;&#x4E3B;&#x8981;&#x901A;&#x8FC7;&#x8C03;&#x5236;&#x7684;&#x5956;&#x52B1;&#x5C5E;&#x6027;&#x7684;&#x98DF;&#x7269;&#x7F8E;&#x5473;&#x98DF;&#x54C1;&#x6D88;&#x8D39;&#x3002;N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) &#x662F;&#x4E00;&#x5957;&#x65B0;&#x578B;&#x963F;&#x7247;&#x53D7;&#x4F53;&#x7684;&#x9006;&#x663E;&#x6548;&#x836F;&#xFF0C;&#x4F53;&#x5916;&#x4EB2;&#x548C;&#x6D4B;&#x5B9A;&#x7684;&#x57FA;&#x7840;&#x4E0A;&#x662F;&#x6BD4; 10-&#x6216; 50 &#x500D;&#x5927;&#x9009;&#x62E9;&#x6027;&#x7684;&#x4EBA;&#x6743;&#x6216;&#x5927;&#x9F20;&#x94C1;&#x9053;&#x90E8;&#x5206;&#x522B;&#x4E0E; &kappa;-&#x963F;&#x7247;&#x53D7;&#x4F53; (&#x5927;&#x97E9;&#x6C11;&#x56FD;) &#x548C; &delta;-&#x963F;&#x7247;&#x53D7;&#x4F53; &#xFF08;DOR&#xFF09; &#x76F8;&#x6BD4;&#x3002;&#x540C;&#x6837;&#xFF0C;&#x4E0E;&#x5927;&#x97E9;&#x6C11;&#x56FD;&#x53CA; DOR &#x4F18;&#x60E0; MOR &#x5360;&#x7528;&#x7EA2;&#x6F6E;&#x4ECE;&#x53E3;&#x5934;&#x4E0E;&#x836F;&#x7269;&#x5927;&#x5242;&#x91CF;&#x957F;&#x57C3;&#x6587;&#x65AF;&#x5927;&#x9F20;&#x8111;&#x7247;&#x653E;&#x5C04;&#x81EA;&#x663E;&#x5F71;&#x3002;GSK1521498 &#x538B;&#x5236;&#x6807;&#x51C6;&#x6216;&#x53EF;&#x53E3;&#x5468;&#x6881;&#x6DD1;&#x6021;&#x8BAE;&#x5458;&#x7CBE;&#x76CA;&#x548C;&#x996E;&#x98DF;&#x8BF1;&#x5BFC;&#x80A5;&#x80D6;&#x5927;&#x9F20; (&#x8FEA;&#x5965;) &#x957F;&#x57C3;&#x6587;&#x65AF;&#x591C;&#x95F4;&#x98DF;&#x54C1;&#x7684;&#x6D88;&#x8D39;&#x3002;&#x4E0E; &mu; &#x53D7;&#x4F53;&#x5360;&#x7528;&#x548C;&#x836F;&#x7269;&#x7684;&#x8840;&#x6D46;&#x6D53;&#x5EA6;&#x5206;&#x5E03;&#x5173;&#x8054;&#x7684;&#x5242;&#x91CF;-&#x53CD;&#x5E94;&#x5173;&#x7CFB;&#x548C;&#x7F8E;&#x8054;&#x50A8;&#x9002;&#x53E3;&#x5468;&#x6881;&#x6DD1;&#x6021;&#x8BAE;&#x5458;&#x7684;&#x7CBE;&#x76CA;&#x5927;&#x9F20;&#x7597;&#x6548;&#x7684;&#x65F6;&#x7A0B;&#x3002;GSK1521498 &#x6162;&#x6027;&#x53E3;&#x670D;&#x81F4;&#x5927;&#x9F20; dio &#x4E0B;&#x5C5E;&#x516C;&#x53F8;&#xFF0C;&#x5176;&#x4E2D;&#x5305;&#x62EC;&#x8102;&#x80AA;&#x5927;&#x89C4;&#x6A21;&#x51CF;&#x5C11;&#x4F53;&#x91CD;&#x3002;&#x4F53;&#x91CD;&#x5728;&#x51CF;&#x5C11;&#xFF0C;&#x8FD9;&#x662F;&#x76F8;&#x5F53;&#x4E8E;&#x7D2F;&#x79EF;&#x51CF;&#x5C11;&#x98DF;&#x54C1;&#x6D88;&#x8D39; &#xFF1B;&#x56E0;&#x6B64;&#xFF0C;&#x5BF9;&#x4F53;&#x91CD; GSK1521498 &#x7684;&#x5F71;&#x54CD;&#x88AB;&#x6709;&#x5173;&#x98DF;&#x54C1;&#x6D88;&#x8D39;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x3002;GSK1521498 &#x538B;&#x5236;&#x504F;&#x7231;&#x542B;&#x6709;&#x8517;&#x7CD6;&#x7684;&#x7CBE;&#x76CA;&#x5927;&#x9F20;&#x7684;&#x89E3;&#x51B3;&#x65B9;&#x6848;&#x3002;GSK1521498 &#x8FD8;&#x4F7F;&#x7528;&#x7CBE;&#x76CA;&#x5927;&#x9F20;&#x80DA;&#x80CE;&#x53CD;&#x5E94;&#x6A21;&#x5F0F;&#xFF0C;&#x51CF;&#x5C11;&#x53EF;&#x53E3;&#x98DF;&#x54C1;&#x5956;&#x52B1;&#x4E0E;&#x589E;&#x5F3A;&#x7684;&#x9971;&#x7684;&#x52A0;&#x56FA;&#x6548;&#x679C;&#x3002;&#x6700;&#x540E;&#xFF0C;GSK1521498 &#x662F;&#x6444;&#x5165;&#x7684;&#x70C8;&#x6027;&#x3001; &#x94C1;&#x9053;&#x90E8;&#x9009;&#x62E9;&#x6027;&#x7684;&#x53CD;&#x5411;&#x6FC0;&#x52A8;&#x5242;&#x8C03;&#x8282;&#x7684;&#x4EAB;&#x4E50;&#x65B9;&#x9762;&#xFF0C;&#x5E76;&#x56E0;&#x6B64;&#xFF0C;&#x53EF;&#x4EE5;&#x8868;&#x793A;&#x836F;&#x7406;&#x6CBB;&#x7597;&#x80A5;&#x80D6;&#x548C;&#x7F8E;&#x996E;&#x98DF;&#x7D0A;&#x4E71;&#x3002;

Ingestive GSK1521498&#xFF0C;&#x65B0;&#x578B;&#x7684;&#x5FAE;-&#x963F;&#x7247;&#x53D7;&#x4F53;&#x9009;&#x62E9;&#x6027;&#x53CD;&#x5411;&#x6FC0;&#x52A8;&#x5242;&#x7684;&#x5927;&#x9F20;&#x7684;&#x884C;&#x4E3A;&#x7684;&#x89C4;&#x7BA1;&#x3002;

Î¼-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with Îº-opioid receptors (KOR) and Î´-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with Î¼ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist.

Agoniste des r&eacute;cepteurs opio&iuml;des &mu; (MOR) induit la consommation d&#39;aliments agr&eacute;ables au go&ucirc;t principalement par la modulation des propri&eacute;t&eacute;s enrichissantes de nourriture. N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-BIPHENYLYL]methyl}-2,3-DIHYDRO-1H-inden-2-amine (GSK1521498) est un agoniste inverse de nouveaux r&eacute;cepteurs opio&iuml;des qui, sur la base des tests d&#39;affinit&eacute; in vitro, est plus grand que 10 ou 50 fois s&eacute;lectif pour homme ou rat MOR, respectivement, compar&eacute;e &agrave; r&eacute;cepteurs opio&iuml;des (KOR) et de r&eacute;cepteurs &delta;-opio&iuml;des (DOR). De m&ecirc;me, pr&eacute;f&eacute;rentielle occupation MOR versus KOR et DOR a &eacute;t&eacute; observ&eacute;e par autoradiographie dans des tranches de cerveau de rats Long Evans ayant re&ccedil;u des doses par voie orale avec la drogue. GSK1521498 a supprim&eacute; la consommation d&#39;aliments nocturnes de chow standard ou acceptable chez les rats Long Evans (DIO) ob&egrave;ses maigres et induite par l&#39;alimentation. La relation dose-effet et &eacute;volution temporelle de l&#39;efficacit&eacute; en maigres rats nourri app&eacute;tant chow en corr&eacute;lation avec l&#39;occupation des r&eacute;cepteurs &mu; et le profil de concentration plasmatique du m&eacute;dicament. Administration orale chronique de GSK1521498 induite par la perte de poids corporel chez les rats DIO, qui comprend la r&eacute;duction massive de la graisse. La r&eacute;duction du poids corporel &eacute;tait &eacute;quivalente &agrave; la r&eacute;duction cumulative de la consommation d&#39;aliments ; ainsi, l&#39;effet du GSK1521498 sur le poids corporel est li&eacute;e &agrave; l&#39;inhibition de la consommation d&#39;aliments. GSK1521498 supprim&eacute;e la pr&eacute;f&eacute;rence pour le saccharose contenant des solutions dans les rats maigres. Dans les mod&egrave;les de r&eacute;action op&eacute;rante aussi &agrave; l&#39;aide de rats maigres, GSK1521498 r&eacute;duit l&#39;efficacit&eacute; de renfort de r&eacute;compense alimentaire app&eacute;tant et sati&eacute;t&eacute; am&eacute;lior&eacute;e. En conclusion, le GSK1521498 est un agoniste inverse puissant, MOR-s&eacute;lective qui module les aspects h&eacute;doniques d&#39;ingestion et, par cons&eacute;quent, pourrait repr&eacute;senter un traitement pharmacologique pour l&#39;ob&eacute;sit&eacute; et les troubles de boulimie.

R&eacute;glementation des comportements alimentaire chez le rat par GSK1521498, un nouveau micro-opio&iuml;de s&eacute;lectif du r&eacute;cepteur agoniste inverse.

&Mu;-Opioid-Rezeptor (MOR) Agonismus induziert schmackhaft Lebensmittelkonsum haupts&auml;chlich durch Modulation der lohnenden Eigenschaften der Lebensmittel. N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]Methyl}-2,3-dihydro-1H-Inden-2-Amine (GSK1521498) ist eine inverse Roman opioid-Rezeptor-Agonist, die auf der Grundlage von in-vitro-Affinit&auml;t Proben, gr&ouml;&szlig;er als 10 oder 50 - 8-fach ist selektiv f&uuml;r Mensch oder Ratte MOR, bzw. gegen&uuml;ber &kappa;-Opioid-Rezeptoren (KOR) und &delta;-Opioid-Rezeptoren (DOR). Ebenso wurde die bevorzugte MOR Belegung versus KOR und DOR durch Autoradiographie im Gehirn Scheiben aus langen Evans Ratten Oral dosiert mit der Droge beobachtet. GSK1521498 unterdr&uuml;ckt n&auml;chtlichen Nahrungsaufnahme von Standard- oder schmackhaft Chow schlank und Di&auml;t-induzierte fettleibig (DIO) lange Evans-Ratten. Die Dosis-Wirkungs-Beziehung und den zeitlichen Verlauf der Wirksamkeit bei schlanken Ratten gef&uuml;ttert schmackhaft Chow korreliert mit &mu;-Rezeptor-Belegung und die Plasma-Konzentration-Profil des Medikaments. Chronischer oraler Gabe von GSK1521498 induziert K&ouml;rper-Gewicht-Verlust bei DIO Ratten, die Masse Fettreduktion umfasste. Die Reduzierung des K&ouml;rpergewichts entsprach die kumulative Verringerung der Nahrungsaufnahme; Daher bezieht sich die Wirkung des GSK1521498 auf K&ouml;rpergewicht auf Hemmung der Nahrungsaufnahme. GSK1521498 unterdr&uuml;ckt die Vorliebe f&uuml;r Saccharose-haltige L&ouml;sungen bei schlanken Ratten. Operante Reaktion-Modelle auch mit schlanke Ratten reduziert GSK1521498 die Verst&auml;rkung-Wirksamkeit von schmackhaft Essen Belohnung und verst&auml;rkten S&auml;ttigungsgef&uuml;hl. GSK1521498 ist ein potenter, MOR-selektive inverse-Agonist, der moduliert die hedonische Aspekte der Einnahme und daher k&ouml;nnte eine pharmakologische Behandlung von Adipositas und ESSSUCHT-Erkrankungen darstellen.

Verordnung der Ansaug Verhaltensweisen bei der Ratte durch GSK1521498, einen Roman Mikro-Opioid-Rezeptor-selektive inverse Agonisten.

Agonismo recettore &mu;-oppioidi (MOR) induce il consumo di cibo appetibile principalmente attraverso la modulazione delle propriet&agrave; gratificante del cibo. N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) &egrave; un agonista inverso del romanzo dei recettori oppioidi che, sulla base di analisi di affinit&agrave; in vitro, &egrave; maggiore rispetto a 10 - o 50 volte selettiva per umani o ratto MOR, rispettivamente, rispetto ai recettori &kappa;-opioid (KOR) e recettori &delta;-opioid (DOR). Similarmente, preferenziale occupancy MOR versus KOR e DOR &egrave; stato osservato da autoradiografia in fettine di cervello da ratti lungo Evans dosati per via orale con il farmaco. GSK1521498 soppresso consumi alimentari notturni di chow standard o appetibile in magri e indotta da dieta obesi ratti lungo Evans (DIO). La relazione dose-risposta e il decorso dell&#39;efficacia in magri ratti alimentati chow appetibile correlato con l&#39;occupazione del recettore &mu; e il profilo di concentrazione del plasma del farmaco. La somministrazione orale cronica di GSK1521498 indotta da perdita di peso del corpo in ratti di Dione, che comprendeva la riduzione della massa grassa. La riduzione del peso corporeo era equivalente alla riduzione cumulativa nel consumo alimentare; cos&igrave;, l&#39;effetto di GSK1521498 sul peso corporeo &egrave; legato alla inibizione del consumo di cibo. GSK1521498 soppresso la preferenza per saccarosio contenenti soluzioni nei ratti magri. Nei modelli di risposta operante anche utilizzando ratti magri, GSK1521498 ridotto l&#39;efficacia di rinforzo del cibo appetibile ricompensa e una maggiore saziet&agrave;. In conclusione, GSK1521498 &egrave; un potente, MOR-selettivo agonista inverso che modula gli aspetti edonistico dell&#39;ingestione e, pertanto, potrebbe rappresentare una terapia farmacologica per l&#39;obesit&agrave; e binge-eating disorders.

Regolamento dei comportamenti ingestive nel ratto di GSK1521498, un romanzo micro-oppioidi selettivo del recettore agonista inverso.

&Mu;-&#x30AA;&#x30D4;&#x30AA;&#x30A4;&#x30C9;&#x53D7;&#x5BB9;&#x4F53; (MOR) &#x4F5C;&#x52D5;: &#x7F8E;&#x5473;&#x3057;&#x3044;&#x98DF;&#x7CE7;&#x6D88;&#x8CBB;&#x98DF;&#x54C1;&#x306E;&#x3084;&#x308A;&#x304C;&#x3044;&#x306E;&#x3042;&#x308B;&#x7279;&#x6027;&#x306E;&#x5909;&#x8ABF;&#x3092;&#x901A;&#x3057;&#x3066;&#x4E3B;&#x3092;&#x8A98;&#x5C0E;&#x3057;&#x307E;&#x3059;&#x3002;N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) &#x306F;, in vitro &#x89AA;&#x548C;&#x6027;&#x30A2;&#x30C3;&#x30BB;&#x30A4;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066; 10 &#x301C; &#x307E;&#x305F;&#x306F; 50 &#x500D;&#x3088;&#x308A;&#x3082;&#x5927;&#x304D;&#x3044;&#x65B0;&#x898F;&#x30AA;&#x30D4;&#x30AA;&#x30A4;&#x30C9;&#x53D7;&#x5BB9;&#x4F53;&#x9006;&#x4F5C;&#x52D5;&#x85AC;&#x3067;&#x3042;&#x308B;&#x4EBA;&#x9593;&#x306E;&#x9078;&#x629E;&#x7684;&#x307E;&#x305F;&#x306F;&#x30E9;&#x30C3;&#x30C8; MOR &#x305D;&#x308C;&#x305E;&#x308C;&#x306B;&#x6BD4;&#x3079;&#x3066; &kappa; &#x30AA;&#x30D4;&#x30AA;&#x30A4;&#x30C9;&#x53D7;&#x5BB9;&#x4F53; (KOR) &#x3068; &delta;-&#x30AA;&#x30D4;&#x30AA;&#x30A4;&#x30C9;&#x53D7;&#x5BB9;&#x4F53; &#xFF08;DOR)&#x3002;&#x540C;&#x69D8;&#x306B;&#x3001;&#x512A;&#x9047; MOR &#x5360;&#x6709;&#x5BFE; KOR &#x3068; DOR &#x306F;&#x7D4C;&#x53E3;&#x6295;&#x4E0E;&#x85AC;&#x3067;&#x9577;&#x3044;&#x30A8;&#x30D0;&#x30F3;&#x30B9; &#x30E9;&#x30C3;&#x30C8;&#x8133;&#x30B9;&#x30E9;&#x30A4;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30AA;&#x30FC;&#x30C8;&#x30E9;&#x30B8;&#x30AA;&#x30B0;&#x30E9;&#x30D5;&#x30A3;&#x30FC;&#x306B;&#x3088;&#x3063;&#x3066;&#x89B3;&#x5BDF;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;GSK1521498 &#x306F;&#x3001;&#x6A19;&#x6E96;&#x307E;&#x305F;&#x306F;&#x53E3;&#x5F53;&#x305F;&#x308A;&#x306E;&#x98DF;&#x4E8B;&#x8D64;&#x8EAB;&#x3068;&#x98DF;&#x990C;&#x8A98;&#x5C0E;&#x6027;&#x80A5;&#x6E80; &#xFF08;DIO&#xFF09; &#x9577;&#x3044;&#x30A8;&#x30D0;&#x30F3;&#x30B9; &#x30E9;&#x30C3;&#x30C8;&#x306E;&#x591C;&#x884C;&#x6027;&#x98DF;&#x54C1;&#x6D88;&#x8CBB;&#x6291;&#x5236;&#x3002;&#x7528;&#x91CF;-&#x53CD;&#x5FDC;&#x95A2;&#x4FC2;&#x3068;&#x6642;&#x9593;&#x30B3;&#x30FC;&#x30B9;&#x53E3;&#x5F53;&#x305F;&#x308A;&#x306E;&#x98DF;&#x4E8B;&#x8D64;&#x8EAB;&#x30E9;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x52B9;&#x529B;&#x306E; &mu; &#x53D7;&#x5BB9;&#x4F53;&#x7D50;&#x5408;&#x5360;&#x6709;&#x3068;&#x85AC;&#x306E;&#x8840;&#x6F3F;&#x6FC3;&#x5EA6;&#x5206;&#x5E03;&#x3068;&#x76F8;&#x95A2;&#x3002;GSK1521498 &#x306E;&#x6162;&#x6027;&#x7D4C;&#x53E3;&#x6295;&#x4E0E;&#x4F53;&#x91CD;&#x6E1B;&#x5C11;&#x8102;&#x80AA;&#x8CEA;&#x91CF;&#x6E1B;&#x5C11;&#x304B;&#x3089;&#x6210;&#x308B; DIO &#x30E9;&#x30C3;&#x30C8;&#x8A98;&#x767A;&#x3002;&#x4F53;&#x91CD;&#x306E;&#x6E1B;&#x5C11;&#x306F;&#x3001;&#x98DF;&#x54C1;&#x306E;&#x6D88;&#x8CBB;&#x91CF;&#x306E;&#x7D2F;&#x7A4D;&#x524A;&#x6E1B;&#x306B;&#x76F8;&#x5F53;&#x3057;&#x305F;;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x4F53;&#x91CD;&#x306B;&#x53CA;&#x307C;&#x3059; GSK1521498 &#x98DF;&#x54C1;&#x6D88;&#x8CBB;&#x6291;&#x5236;&#x306B;&#x95A2;&#x9023;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;GSK1521498 &#x6291;&#x5236;&#x597D;&#x307F;&#x306E;&#x30B7;&#x30E7;&#x7CD6;&#x3092;&#x542B;&#x3080;&#x305F;&#x3081;&#x30EA;&#x30FC;&#x30F3; &#x30E9;&#x30C3;&#x30C8;&#x306E;&#x30BD;&#x30EA;&#x30E5;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3002;&#x307E;&#x305F;&#x30EA;&#x30FC;&#x30F3;&#x306E;&#x30E9;&#x30C3;&#x30C8;&#x3092;&#x7528;&#x3044;&#x305F;&#x30AA;&#x30DA;&#x30E9;&#x30F3;&#x30C8;&#x53CD;&#x5FDC;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;GSK1521498 &#x7F8E;&#x5473;&#x3057;&#x3044;&#x98DF;&#x7CE7;&#x5831;&#x916C;&#x3068;&#x5F37;&#x5316;&#x3055;&#x308C;&#x305F;&#x6E80;&#x8179;&#x306E;&#x88DC;&#x5F37;&#x52B9;&#x679C;&#x3092;&#x4F4E;&#x6E1B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x3001;GSK1521498 &#x306F;&#x3001;&#x6442;&#x53D6;&#x306E;&#x5FEB;&#x697D;&#x306E;&#x5074;&#x9762;&#x3092;&#x30E2;&#x30B8;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3057;&#x3001;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x80A5;&#x6E80;&#x3001;&#x904E;&#x98DF;&#x969C;&#x5BB3;&#x306E;&#x85AC;&#x7406;&#x5B66;&#x7684;&#x6CBB;&#x7642;&#x3092;&#x8868;&#x3059;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x5F37;&#x529B;&#x306A; MOR &#x9078;&#x629E;&#x7684;&#x9006;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x3067;&#x3059;&#x3002;

GSK1521498 &#x65B0;&#x898F;&#x30DE;&#x30A4;&#x30AF;&#x30ED;-&#x30AA;&#x30D4;&#x30AA;&#x30A4;&#x30C9;&#x53D7;&#x5BB9;&#x4F53;&#x9078;&#x629E;&#x7684;&#x9006;&#x4F5C;&#x52D5;&#x85AC;&#x306B;&#x3088;&#x308B;&#x30E9;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x6442;&#x98DF;&#x884C;&#x52D5;&#x306E;&#x898F;&#x5236;&#x3002;

&Mu;-Opioid &#xC218;&#xC6A9; &#xCCB4; (MOR) agonism &#xC74C;&#xC2DD;&#xC758; &#xBCF4;&#xB78C; &#xC18D;&#xC131;&#xC758; &#xBCC0;&#xC870;&#xB97C; &#xD1B5;&#xD574; &#xC8FC;&#xB85C; &#xC785; &#xC2DD;&#xD488; &#xC18C;&#xBE44;&#xB97C; &#xC720;&#xB3C4; &#xD55C;&#xB2E4;. N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498)&#xC740; &#xAE38; &#xD56D; &#xD55C; &#xC18C;&#xC124; opioid &#xC218;&#xC6A9; &#xCCB4; &#xC5ED; &#xC81C; &#xCCB4; &#xC678; &#xC120;&#xD638;&#xB3C4; &#xBD84;&#xC11D; &#xC2E4;&#xD5D8;, &#xAE30;&#xCD08; &#xD06C;&#xBA74; &#xBCF4;&#xB2E4; 10-&#xB610;&#xB294; 50 &#xBC30;&#xB294; &#xC778; &#xAC04;&#xC5D0; &#xB300; &#xD55C; &#xC120;&#xD0DD;&#xC801; &#xB610;&#xB294; &#xC950; MOR, &#xAC01;&#xAC01;, &kappa;-opioid &#xC218;&#xC6A9; &#xCCB4; (KOR) &#xBC0F; &delta;-opioid &#xC218;&#xC6A9; &#xCCB4; (DOR)&#xC640; &#xBE44;&#xAD50; &#xD569;&#xB2C8;&#xB2E4;. &#xB9C8;&#xCC2C;&#xAC00;&#xC9C0;&#xB85C;, KOR&#xACFC;&#xB3C4; &#xB974; &#xB300; &#xC6B0;&#xB300; MOR &#xC778; &#xAD6C;&#xB450; &#xC57D;&#xC73C;&#xB85C; &#xC57D;&#xC744; &#xBCF5;&#xC6A9; &#xD558;&#xB294; &#xAE34; &#xC5D0;&#xBC18;&#xC2A4; &#xC950;&#xC5D0;&#xC11C; &#xB1CC; &#xC870;&#xAC01;&#xC5D0;&#xC11C; autoradiography &#xD558; &#xC5EC; &#xAD00;&#xCC30; &#xB418;&#xC5C8;&#xB2E4;. GSK1521498 &#xD45C;&#xC900; &#xB610;&#xB294; &#xC785; &#xC6B0; &#xC57C; &#xC704; &#xACE0; &#xB2E4;&#xC774;&#xC5B4;&#xD2B8; &#xC720;&#xBC1C; &#xB41C; &#xBE44;&#xB9CC; (DIO) &#xAE34; &#xC5D0;&#xBC18;&#xC2A4; &#xC950;&#xC758; &#xC57C;&#xD589;&#xC131; &#xC2DD;&#xD488; &#xC18C;&#xBE44;&#xB97C; &#xC5B5;&#xC81C;. &#xBCF5;&#xC6A9;&#xB7C9;-&#xBC18;&#xC751; &#xAD00;&#xACC4; &#xBC0F; &#xBA39;&#xC774; &#xC785; &#xC6B0; &#xB9B0; &#xC950;&#xC5D0; &#xD6A8;&#xB2A5;&#xC758; &#xC2DC;&#xAC04; &#xACFC;&#xC815; &mu; &#xC218;&#xC6A9; &#xCCB4; &#xC778; &#xACE0; &#xC57D;&#xC758; &#xD50C;&#xB77C;&#xC988;&#xB9C8; &#xB18D;&#xB3C4; &#xD504;&#xB85C; &#xD30C;&#xC77C; &#xC0C1;&#xD638; &#xC5F0;&#xAD00;. Gsk1521498&#xC758; &#xB9CC;&#xC131; &#xAD6C;&#xAC15; &#xAD00;&#xB9AC; &#xC9C0;&#xBC29; &#xC9C8;&#xB7C9; &#xAC10;&#xC18C; &#xAD6C;&#xC131; DIO &#xC950;&#xC5D0;&#xC11C; &#xBAB8; &#xCCB4;&#xC911; &#xAC10;&#xC18C; &#xC720;&#xBC1C;. &#xBAB8; &#xBB34;&#xAC8C;&#xC758; &#xAC10;&#xC18C;&#xB294; &#xD574;&#xB2F9; &#xC2DD;&#xD488; &#xC18C;&#xBE44;; &#xB204;&#xC801; &#xAC10;&#xC18C; &#xD558; &#xB530;&#xB77C;&#xC11C;, &#xBAB8; &#xBB34;&#xAC8C; GSK1521498 &#xC601;&#xD5A5;&#xB3C4; &#xC2DD;&#xD488; &#xC18C;&#xBE44;&#xC758; &#xC5B5;&#xC81C; &#xAD00;&#xB828;&#xC774; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. GSK1521498 &#xC5B5;&#xC81C; &#xC790;&#xB2F9;&#xC774; &#xD3EC;&#xD568; &#xB41C;&#xC5D0; &#xB300; &#xD55C; &#xAE30;&#xBCF8; &#xC124;&#xC815; &#xB9C8;&#xB978; &#xC950;&#xC5D0; &#xC194;&#xB8E8;&#xC158;. &#xB610;&#xD55C; &#xB9C8;&#xB978; &#xC950;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xC791;&#xB3D9; &#xC751;&#xB2F5; &#xBAA8;&#xB378;, GSK1521498 &#xC785; &#xC74C;&#xC2DD; &#xBCF4;&#xC0C1; &#xBC0F; &#xD5A5;&#xC0C1; &#xB41C; &#xBB3C;&#xB9BC;&#xC758; &#xBCF4;&#xAC15; &#xD6A8;&#xB2A5; &#xAC10;&#xC18C;. &#xB05D;&#xC73C;&#xB85C;, gsk1521498&#xC740; &#xAE38; &#xD56D;&#xC744; &#xC801; &#xC815;&#xB7C9;, MOR &#xC120;&#xD0DD;&#xC801; &#xC5ED; &#xC81C;&#xB294; &#xC12D;&#xCDE8;&#xC758; &#xCF8C;&#xB77D; &#xCE21;&#xBA74;&#xC744; &#xBCC0;&#xC870; &#xD558; &#xACE0; &#xB530;&#xB77C;&#xC11C; &#xBE44;&#xB9CC; &#xC9C4; &#xD0D5; &#xC2DD;&#xC0AC; &#xC7A5;&#xC560;&#xC5D0; &#xB300; &#xD55C; &#xC57D;&#xB9AC; &#xCE58;&#xB8CC;&#xB97C; &#xB098;&#xD0C0;&#xB0BC; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

GSK1521498, &#xAE38; &#xD56D; &#xD55C; &#xC18C;&#xC124; &#xB9C8;&#xC774;&#xD06C;&#xB85C; opioid &#xC218;&#xC6A9; &#xCCB4; &#xC120;&#xD0DD;&#xC801; &#xC5ED; &#xC81C; &#xD558; &#xC5EC; &#xC950; ingestive &#xD589;&#xB3D9;&#xC758; &#xADDC;&#xC81C;.

Agonismo del receptor opioide &mu; (MOR) induce aceptable consumo principalmente a trav&eacute;s de la modulaci&oacute;n de las propiedades adictivas de la comida. N-{[3,5-Difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-Biphenylyl]Methyl}-2,3-dihydro-1H-Inden-2-Amine (GSK1521498) es un agonista inverso de receptores opioides novela que, sobre la base de ensayos de afinidad in vitro, es mayor que 10 o 50 veces selectiva para humanos o rata MOR, respectivamente, en comparaci&oacute;n con los receptores opi&aacute;ceos &kappa; (KOR) y receptores &delta;-opioides (DOR). Asimismo, se observ&oacute; ocupaci&oacute;n preferencial MOR versus KOR y DOR por autorradiograf&iacute;a en rebanadas de cerebro de ratas Long Evans dosificadas por v&iacute;a oral con el f&aacute;rmaco. GSK1521498 suprime el consumo nocturno de chow est&aacute;ndar o aceptable en magras e inducida por dieta ratas obesas de Evans largo (DIO). La relaci&oacute;n dosis-respuesta y el curso temporal de la eficacia en la magras ratas alimentadas chow apetitosas correlacionan con la ocupaci&oacute;n de receptores &mu; y el perfil de la concentraci&oacute;n de plasma de la droga. La administraci&oacute;n oral cr&oacute;nica de GSK1521498 inducida por la p&eacute;rdida de peso corporal en ratas DIO, que inclu&iacute;a la reducci&oacute;n de la masa grasa. La reducci&oacute;n en el peso corporal fue equivalente a la reducci&oacute;n acumulada en el consumo de alimentos; as&iacute;, el efecto de GSK1521498 en el peso corporal se relaciona con la inhibici&oacute;n del consumo de alimentos. GSK1521498 suprimi&oacute; la preferencia para que contengan sacarosa soluciones en ratas magras. En modelos de respuesta operante tambi&eacute;n utilizando ratas magras, GSK1521498 reduce la eficacia del refuerzo de la recompensa de comida sabrosa y mayor saciedad. En conclusi&oacute;n, GSK1521498 es un potente, MOR-selectivo Agonista inverso que modula los aspectos hed&oacute;nicos de ingesti&oacute;n y, por lo tanto, podr&iacute;a representar un tratamiento farmacol&oacute;gico para la obesidad y trastornos de ingesta compulsiva.

Regulaci&oacute;n de comportamientos ingestiva en la rata por GSK1521498, un nuevo micro-opioid receptor selectivo Agonista inverso.

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance.

Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1.

Jonathan D. Hommel

Center for Addiction Research,
Department of Pharmacology and Toxicology,
Center for Addiction Research, Department of Pharmacology and Toxicology

University of Texas Medical Branch

Fat Preference: A Novel Model of Eating Behavior in Rats

Jonathan D. Hommel

Center for Addiction Research,Department of Pharmacology and Toxicology,Center for Addiction Research, Department of Pharmacology and Toxicology

University of Texas Medical Branch

Fat Preference: A Novel Model of Eating Behavior in Rats

Center for Addiction Research,
Department of Pharmacology and Toxicology,
Center for Addiction Research, Department of Pharmacology and Toxicology