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1.
Endocrinology ; 157(12): 4561-4569, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27779915

RESUMO

Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP-1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role.


Assuntos
Colo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Triglicerídeos/metabolismo , Animais , Benzofuranos/farmacologia , Bombesina/farmacologia , Colo/efeitos dos fármacos , Gorduras na Dieta , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/genética , Sulfonas/farmacologia
2.
J Lipid Res ; 52(4): 646-56, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21296956

RESUMO

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.


Assuntos
Gorduras na Dieta/efeitos adversos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Hipolipemiantes/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Obesidade/tratamento farmacológico , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células Cultivadas , Quimiocina CCL2/metabolismo , Dislipidemias/induzido quimicamente , Dislipidemias/tratamento farmacológico , Ácidos Graxos não Esterificados/sangue , Resistência à Insulina , Lipólise/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Obesidade/induzido quimicamente , Triglicerídeos/sangue
3.
Vitam Horm ; 84: 415-48, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21094910

RESUMO

Type 2 diabetes (T2D) has reached epidemic proportions, and there is an unmet medical need for orally effective agents that regulate glucose homeostasis. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor expressed primarily in the pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in recent years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic ß-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY). Oral administration of small molecule GPR119 agonists has been shown to improve glucose tolerance in both rodents and humans. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders, and provides an overview of the recent progress made in the discovery of orally active GPR119 agonists.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Humanos , Hipoglicemiantes/uso terapêutico
4.
PPAR Res ; 2010: 970164, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20445733

RESUMO

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/ 0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.

6.
Expert Opin Ther Pat ; 19(6): 801-25, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19456274

RESUMO

BACKGROUND: The main components of metabolic syndrome (obesity, insulin resistance, hypertension and dyslipidemia) have become prevalent worldwide, and excess glucocorticoid levels have been implicated in patients with these symptoms. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an enzyme involved in glucocorticoid regulation through catalysis of the conversion of inactive cortisone to its active form cortisol. Numerous rodent studies have demonstrated the potential use of 11beta-HSD1 inhibitors as treatment for the components of metabolic syndrome and limited clinical data in humans have shown 11beta-HSD1 inhibition to improve glucose levels, insulin sensitivity and lipid profiles. Many organizations have been active in the 11beta-HSD1 academic and patent literature, and two previous articles from this journal have reviewed disclosures through August 2007. OBJECTIVE: To summarize the recent patent literature and progress in defining the utility of small molecule 11beta-HSD1 inhibitors. METHODS: This review covers the recent 11beta-HSD1 patent literature and clinical activity ranging from late 2007 through the end of 2008. RESULTS/CONCLUSION: The exploration of 11beta-HSD1 inhibitors continues, as a number of structural classes have been reported by several pharmaceutical companies over the past 16 months. Current clinical trials will ultimately shed light on the feasibility of 11beta-HSD1 inhibitors as pharmaceutical agents for the various components of metabolic syndrome.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Resistência à Insulina , Lipídeos/sangue , Síndrome Metabólica/fisiopatologia , Patentes como Assunto
7.
J Endocrinol ; 201(2): 219-30, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19282326

RESUMO

G protein-coupled receptor 119 (GPR119) is expressed in pancreatic islets and intestine, and is involved in insulin and incretin hormone release. GPR119-knockout (Gpr119(-/-)) mice were reported to have normal islet morphology and normal size, body weight (BW), and fed/fasted glucose levels. However, the physiological function of GPR119 and its role in maintaining glucose homeostasis under metabolic stress remain unknown. Here, we report the phenotypes of an independently generated line of Gpr119(-/-) mice under basal and high-fat diet (HFD)-induced obesity. Under low-fat diet feeding, Gpr119(-/-) mice show normal plasma glucose and lipids, but have lower BWs and lower post-prandial levels of active glucagon-like peptide 1 (GLP-1). Nutrient-stimulated GLP-1 release is attenuated in Gpr119(-/-) mice, suggesting that GPR119 plays a role in physiological regulation of GLP-1 secretion. Under HFD-feeding, both Gpr119(+)(/)(+) and Gpr119(-/-) mice gain weight similarly, develop hyperinsulinemia and hyperleptinemia, but not hyperglycemia or dyslipidemia. Glucose and insulin tolerance tests did not reveal a genotypic difference. These data show that GPR119 is not essential for the maintenance of glucose homeostasis. Moreover, we found that oleoylethanolamide (OEA), reported as a ligand for GPR119, was able to suppress food intake in both Gpr119(+)(/)(+) and Gpr119(-/-) mice, indicating that GPR119 is not required for the hypophagic effect of OEA. Our results demonstrate that GPR119 is important for incretin and insulin secretion, but not for appetite suppression.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Homeostase/genética , Redes e Vias Metabólicas/genética , Receptores Acoplados a Proteínas G/fisiologia , Via Secretória/genética , Animais , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/genética , Células Cultivadas , Endocanabinoides , Feminino , Marcação de Genes , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Incretinas/metabolismo , Incretinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lisofosfatidilcolinas/metabolismo , Lisofosfatidilcolinas/farmacologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácidos Oleicos/metabolismo , Ácidos Oleicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Via Secretória/efeitos dos fármacos
8.
BioDrugs ; 21(5): 311-21, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17896837

RESUMO

There is compelling genetic and pharmacologic evidence to indicate that melanin-concentrating hormone receptor-1 (MCHR1) signaling is involved in the regulation of food intake and energy expenditure. The medical need for novel therapies to treat obesity and related metabolic disorders has led to a great deal of interest by pharmaceutical companies in the discovery of MCHR1 antagonists. Recent publications describing preclinical studies have demonstrated that small-molecule MCHR1 antagonists decrease food intake, bodyweight, and adiposity in rodent models of obesity. Results from ongoing early-stage clinical trials with MCHR1 antagonists are eagerly awaited, as is the movement of other MCHR1 antagonists into the clinic.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Estrutura Molecular , Obesidade/fisiopatologia , Receptores de Somatostatina/fisiologia , Transdução de Sinais/efeitos dos fármacos
10.
J Med Chem ; 49(7): 2294-310, 2006 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-16570926

RESUMO

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.


Assuntos
Fármacos Antiobesidade/síntese química , Compostos de Fenilureia/síntese química , Piperazinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ingestão de Alimentos/efeitos dos fármacos , Meia-Vida , Masculino , Obesidade/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual , Ureia/farmacologia
11.
Eur J Pharmacol ; 535(1-3): 182-91, 2006 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-16540104

RESUMO

Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Nitrilas/farmacologia , Obesidade/fisiopatologia , Piperazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Tecido Adiposo/efeitos dos fármacos , Administração Oral , Animais , Ligação Competitiva , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Feminino , Galanina/genética , Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Hormônios Hipotalâmicos/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Radioisótopos do Iodo , Leptina/sangue , Masculino , Melaninas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neuropeptídeo Y/genética , Neuropeptídeos/genética , Nitrilas/administração & dosagem , Obesidade/etiologia , Oligopeptídeos/metabolismo , Receptores de Orexina , Orexinas , Piperazinas/administração & dosagem , Hormônios Hipofisários/genética , Ligação Proteica , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/sangue , Ureia/administração & dosagem , Ureia/farmacologia
12.
Bioorg Med Chem ; 14(10): 3285-99, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16442800

RESUMO

Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.


Assuntos
Compostos de Aminobifenil/química , Compostos Bicíclicos com Pontes/química , Heptanos/química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Linhagem Celular , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Heptanos/farmacologia , Camundongos , Estrutura Molecular , Mutagênicos/química , Ratos , Relação Estrutura-Atividade
13.
J Clin Invest ; 115(12): 3484-93, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16284652

RESUMO

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.


Assuntos
Diabetes Mellitus/terapia , Terapia Genética/métodos , Infertilidade/terapia , Neurônios/metabolismo , Obesidade/terapia , Receptores de Superfície Celular/genética , Proteína Relacionada com Agouti , Alelos , Animais , Glicemia/metabolismo , Composição Corporal , Peso Corporal , Temperatura Baixa , DNA Complementar/metabolismo , Diabetes Mellitus/genética , Feminino , Fertilidade , Regulação da Expressão Gênica , Genótipo , Glucose/metabolismo , Homeostase , Homozigoto , Hipotálamo/patologia , Hibridização In Situ , Infertilidade/genética , Infertilidade Feminina/terapia , Infertilidade Masculina/terapia , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Camundongos , Camundongos Transgênicos , Neuropeptídeo Y/genética , Obesidade/genética , Peptídeos/química , Fenótipo , Fosfopiruvato Hidratase/genética , Reação em Cadeia da Polimerase , Pró-Opiomelanocortina/genética , Regiões Promotoras Genéticas , Isoformas de Proteínas , Proteínas/genética , Ratos , Receptores para Leptina , Transdução de Sinais , Sinapsinas/genética , Fatores de Tempo , Distribuição Tecidual , Transgenes
14.
J Med Chem ; 48(15): 4746-9, 2005 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-16033253

RESUMO

Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.


Assuntos
Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Doença Crônica , Humanos , Obesidade/metabolismo , Ratos , Receptores de Somatostatina/genética , Relação Estrutura-Atividade , Ureia/farmacologia
15.
J Med Chem ; 48(7): 2274-7, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15801820
16.
Expert Opin Investig Drugs ; 13(9): 1113-22, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15330743

RESUMO

The compelling genetic and pharmacological evidence implicating melanin-concentrating hormone-1 receptor (MCH-1R) signalling in the regulation of food intake and energy expenditure has generated a great deal of interest by pharmaceutical companies for the discovery of MCH-1R antagonists, evidenced by the increased number of patents describing MCH-1R antagonists for the treatment of obesity and metabolic syndrome. The structural diversity of small molecular weight drug-like MCH-1R antagonists produced and preclinical studies showing hypophagia and weight loss with small molecular weight and peptidal antagonists in rodents is encouraging and suggests that the identification of clinical candidates will be forthcoming.


Assuntos
Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/uso terapêutico , Animais , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Estrutura Molecular , Receptores de Somatostatina/química
17.
Eur J Pharmacol ; 497(1): 41-7, 2004 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-15321733

RESUMO

Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (-)enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4 carboxamide). Food intake was continuously monitored for 24 h using a BioDAQ food intake monitoring system. A total of 10 mg/kg T-226296 significantly decreased body weight and 24-h food intake, and had no effect on locomotor activity. The decrease in food intake was due to a reduction in meal size, not meal frequency. We conclude that MCH-1 receptor antagonism with T-226296 decreases food intake in DIO rats by selectively reducing meal size, and that the reduced food intake is not due to a generalized behavioral malaise.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacologia , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Fatores de Tempo
18.
Appetite ; 42(1): 11-4, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15036778

RESUMO

The risk for developing obesity has a significant genetic component. Several quantitative trait loci and candidate genes have been identified using current methodological approaches however the information gained thus far is insufficient to adequately explain the genetics underlying human obesity. The completion of a draft of the human genome sequence, the potential benefit of single nucleotide polymorphisms association studies for identifying risk conferring alleles, and developing functional genomics technologies promise to accelerate obesity gene discovery. These advances, used with current evaluative tools (murine molecular genetic techniques), may increase our understanding of human obesity, and ultimately provide better approaches to diagnosis and treatment.


Assuntos
Apetite/genética , Genoma Humano , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Comportamento Alimentar , Humanos , Locos de Características Quantitativas , Fatores de Risco
19.
Obes Res ; 11(7): 845-51, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12855753

RESUMO

OBJECTIVE: To characterize the meal patterns of free feeding Sprague-Dawley rats that become obese or resist obesity when chronically fed a high-fat diet. RESEARCH METHODS AND PROCEDURES: Male Sprague-Dawley rats (N = 120) were weaned onto a high-fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet-induced obese (DIO)] and lower [diet-resistant (DR)] deciles for body-weight gain were selected for study. A cohort of chow-fed (CF) rats weight-matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. RESULTS: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. DISCUSSION: The hyperphagia of a Sprague-Dawley rat model of chronic diet-induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.


Assuntos
Dieta , Alimentos , Predisposição Genética para Doença , Obesidade/etiologia , Obesidade/genética , Animais , Composição Corporal , Ritmo Circadiano , Ingestão de Alimentos , Ingestão de Energia , Hiperglicemia/etiologia , Hiperinsulinismo/etiologia , Hiperfagia , Hipertrigliceridemia/etiologia , Insulina/sangue , Leptina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Saciação , Aumento de Peso
20.
Physiol Behav ; 78(4-5): 517-20, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12782203

RESUMO

An increased action of hypothalamic neuropeptide Y (NPY) has been proposed as a major factor in the pathophysiology of the obesity syndrome in Zucker (fa/fa) rats. Using a developmental strategy to test this hypothesis, we showed previously that significantly more arcuate NPY was expressed in fa/fa pups than in lean littermates on postnatal day (P) 2 and throughout the preweaning period [Physiol. Behav. 67 (1999) 521], and that hyperphagia first appeared on P12 [Am. J. Physiol. 275 (1998) R1106]. To test the hypothesis further, we used a specific radioimmunoassay to measure the concentration of hypothalamic NPY peptide in lean (+/+ and +/fa) and obese fa/fa Zucker rat pups on P9, P10, and P12. The concentration of NPY in fa/fa pups was not significantly different from that of the other genotypes. There was, however, a significant decrease in NPY concentration from P9 to P12 in fa/fa pups, but not in lean pups. The combination of increased NPY message and decreasing concentration of NPY peptide in fa/fa pups with age is consistent with, but does not prove, increased release of hypothalamic NPY in fa/fa pups just before and on P12 when hyperphagia emerges. These results provide further support for the importance of hypothalamic NPY in the phenotypic expression of hyperphagia in the fa/fa pups during the second postnatal week.


Assuntos
Hiperfagia/genética , Hipotálamo/metabolismo , Neuropeptídeo Y/genética , Envelhecimento/fisiologia , Animais , Feminino , Genótipo , Hiperfagia/metabolismo , Hiperfagia/psicologia , Masculino , Neuropeptídeo Y/metabolismo , Obesidade/genética , Obesidade/metabolismo , Obesidade/psicologia , Fenótipo , Ratos , Ratos Zucker
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