Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
Eur J Pharmacol ; 624(1-3): 77-83, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19836369

ABSTRACT

Melanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH(1) receptor in rodents. It is widely considered that MCH(1) receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy assay using a new radiolabeled MCH(1) receptor antagonist, [(35)S]-compound D. An MCH(1) receptor antagonist inhibited the binding of [(35)S]-compound D to brain slices in a dose-dependent manner. The result showed a good correlation between the receptor occupancy levels and plasma or brain levels of the MCH(1) receptor antagonist, suggesting that the ex vivo receptor binding assay using this radioligand is practical. Quantitative analysis in diet-induced obese mice showed that the efficacy of body weight reduction correlated with the receptor occupancy levels at 24h. Furthermore, more than 90% occupancy levels of MCH(1) receptor antagonists during 24h post-dosing are required for potent efficacy on body weight reduction. The present occupancy assay could be a useful pharmacodynamic marker to quantitatively estimate anti-obese efficacy, and would accelerate the development of MCH(1) receptor antagonists for treatment of obesity.


Subject(s)
Anti-Obesity Agents/pharmacology , Obesity/chemically induced , Obesity/drug therapy , Receptors, Pituitary Hormone/antagonists & inhibitors , Weight Gain/drug effects , Animal Feed , Animals , Anti-Obesity Agents/therapeutic use , Diet , Dose-Response Relationship, Drug , Mice , Obesity/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Pituitary Hormone/metabolism , Weight Gain/physiology
2.
Am J Physiol Endocrinol Metab ; 297(6): E1358-65, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19808907

ABSTRACT

Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose-induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg in the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose in the colon did not increase GIP or GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Coadministration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose in the upper intestine blocked glucose absorption and glucose-induced incretin secretion. alpha-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after a 2-h fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a noncalorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Gastric Inhibitory Polypeptide/metabolism , Glucagon-Like Peptide 1/metabolism , Glucose/metabolism , Intestine, Large/metabolism , Sodium-Glucose Transporter 1/metabolism , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Gastric Inhibitory Polypeptide/blood , Gastric Inhibitory Polypeptide/genetics , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/genetics , Glucose Tolerance Test , Hyperglycemia/blood , Hyperglycemia/metabolism , Male , Methylglucosides/metabolism , Mice , Mice, Inbred C57BL , Phlorhizin/pharmacology , RNA, Messenger/chemistry , RNA, Messenger/genetics , Random Allocation , Reverse Transcriptase Polymerase Chain Reaction , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 1/genetics
3.
Expert Opin Ther Pat ; 19(10): 1401-15, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19743896

ABSTRACT

BACKGROUND: Neuropeptide Y (NPY) has been demonstrated to have critical roles in the physiological control of appetite and energy homeostasis through NPY Y1, Y2, Y4 and Y5 receptors. A number of synthetic ligands for NPY receptor subtypes have been developed to date, with Y5 receptor antagonists and Y2 and Y4 receptor agonists advancing into clinical trials. METHODS: A survey of the scientific and patent literature since mid-2006 is presented. CONCLUSION: In addition to the specific modulation of respective NPY receptor subtypes, recent investigations have revealed that modulation of multiple NPY receptor subtypes produces additive or even synergistic anti-obesity effects. Development of reliable small molecule Y1, Y2 and Y4 receptor ligands would greatly accelerate investigations and drug discovery.


Subject(s)
Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Receptors, Neuropeptide Y/drug effects , Animals , Anti-Obesity Agents/chemistry , Drug Design , Humans , Ligands , Molecular Structure , Neuropeptide Y/metabolism , Obesity/metabolism , Receptors, Neuropeptide Y/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship , Treatment Outcome
4.
Eur J Pharmacol ; 615(1-3): 113-7, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19482021

ABSTRACT

Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropeptide Y receptor subtypes have been cloned, and multiple neuropeptide Y receptor subtypes are thought to mediate neuropeptide Y activity. However, interactions among neuropeptide Y receptor subtypes have not been elucidated to date. Herein, we examined the interaction between neuropeptide Y(1) and Y(5) receptors in feeding regulation by employing selective neuropeptide Y(1) and Y(5) receptor antagonists in C57BL/6 and neuropeptide Y(1) receptor knockout mice fed a high-fat diet. A single-dose of a neuropeptide Y(1) receptor antagonist (10-30 mg/kg) suppressed spontaneous food intake and reduced body weight in high-fat diet-fed C57BL/6 mice, while treatment with a neuropeptide Y(5) receptor antagonist did not significantly reduce food intake or body weight. Coadministration of a neuropeptide Y(1) receptor antagonist with a neuropeptide Y(5) receptor antagonist further suppressed food intake and reduced body weight. Next, we evaluated the chronic efficacy of a neuropeptide Y(5) receptor antagonist in high-fat diet-fed neuropeptide Y(1) receptor knockout mice in order to mimic chronic combination treatment with neuropeptide Y(1) and Y(5) receptor antagonists. The neuropeptide Y(5) receptor antagonist produced greater body weight reductions in high-fat diet-fed neuropeptide Y(1) receptor knockout mice than in wild-type C57BL/6 mice. These findings confirm an interaction between neuropeptide Y(1) and Y(5) receptors in the regulation of energy homeostasis, as blockade of both the neuropeptide Y(1) and Y(5) receptors produced a greater anti-obesity effect than blocking either receptor alone.


Subject(s)
Anti-Obesity Agents/pharmacology , Eating/drug effects , Energy Metabolism/physiology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Body Weight/drug effects , Dietary Fats/administration & dosage , Drug Synergism , Homeostasis , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Morpholines/pharmacology , Obesity/drug therapy , Obesity/metabolism , Pyridines/pharmacology , Receptors, Neuropeptide Y/genetics , Spiro Compounds/pharmacology , Thiazoles/pharmacology
5.
J Med Chem ; 52(10): 3385-96, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19459652

ABSTRACT

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.


Subject(s)
Anti-Obesity Agents/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Imidazolines/pharmacology , Obesity/drug therapy , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Brain/metabolism , Cerebrospinal Fluid/metabolism , Disease Models, Animal , Drug Discovery , ERG1 Potassium Channel , Humans , Imidazolines/chemical synthesis , Imidazolines/chemistry , Pharmacokinetics , Protein Binding/drug effects , Rats , Structure-Activity Relationship , Weight Loss/drug effects
6.
Peptides ; 30(7): 1318-22, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19394383

ABSTRACT

Neuropeptide Y (NPY) and its family of peptides are thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, stimulation of the Y2 receptor (Y2R) or inhibition of the Y5 receptor (Y5R) has recently been shown to produce weight-lowering effects in obese rodents. The present study examined and compared the effects of a Y2R agonist, PYY(3-36), and a Y5R antagonist, alone and in combination, on food intake and body weight in diet-induced obese (DIO) mice. Acute intraperitoneal injection of PYY(3-36) dose-dependently reduced spontaneous feeding in lean and DIO mice. In contrast, acute oral administration of the Y5R antagonist had no effect on spontaneous feeding or the anorexigenic effects of PYY(3-36). In a chronic study, subcutaneous infusion of PYY(3-36) (1 mg/kg/day for 14 days) significantly reduced food intake and body weight in DIO mice. The Y5R antagonist (10 mg/kg/day for 14 days, orally) reduced body weight to the same extent as PYY(3-36) without a significant feeding reduction. Combined administration of PYY(3-36) and the Y5R antagonist resulted in a greater body weight reduction than treatment with either agent alone. The combined effects on food intake, body weight, and adiposity are almost the same as a hypothetical sum of the effects of each drug alone. These results illustrate that the combination of a Y2R agonist, PYY(3-36), and a Y5R antagonist resulted in additive effects on body weight and adiposity in DIO mice, suggesting that Y2R stimulation signal and Y5R blockade signal act by distinct pathways.


Subject(s)
Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Obesity , Peptide YY/pharmacology , Receptors, Neuropeptide Y/agonists , Receptors, Neuropeptide Y/antagonists & inhibitors , Adiposity/drug effects , Animals , Dietary Fats/pharmacology , Eating/drug effects , Male , Mice , Mice, Inbred C57BL
7.
Endocrinology ; 150(6): 2668-73, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19196798

ABSTRACT

Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for opioid receptor-like 1 (ORL1), is involved in various central functions, such as pain, psychological stress, locomotor activity, learning and memory, and feeding regulation. Of these functions, the role of N/OFQ in the regulation of feeding has been suggested by the fact that the central administration of N/OFQ leads to feeding behavior. However, the manner in which N/OFQ influences body weight control and subsequent obesity is unclear. To clarify the involvement of N/OFQ in the development of obesity, we evaluated the effects of intracerebroventricular infusion of N/OFQ on food intake and body weight in C57BL/6J mice that were fed a regular chow diet or moderately high-fat (MHF) diet (32.6% kcal fat). N/OFQ significantly increased food intake and body weight both in the regular diet- and MHF diet-fed mice, and these changes were more apparent in the MHF diet-fed mice. When we performed a pair-feeding study in N/OFQ intracerebroventricularly infused mice, N/OFQ did not cause body weight gain but increased white adipose tissue weight and plasma leptin, insulin, and cholesterol levels. N/OFQ reduced rectal temperature in pair-fed mice, in keeping with decreased UCP1 mRNA expression in brown adipose tissue. These results suggest that N/OFQ contributes to the development of obesity not only by inducing hyperphagia but also by decreasing energy expenditure.


Subject(s)
Appetite Regulation/drug effects , Cerebral Ventricles/drug effects , Energy Metabolism/drug effects , Opioid Peptides/pharmacology , Vasodilator Agents/pharmacology , Weight Gain/drug effects , Adipose Tissue, Brown/metabolism , Animals , Appetite Regulation/physiology , Body Weight/drug effects , Body Weight/physiology , Cerebral Ventricles/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Eating/drug effects , Eating/physiology , Energy Metabolism/physiology , Hyperphagia/physiopathology , Infusion Pumps, Implantable , Male , Mice , Mice, Inbred C57BL , Models, Animal , Opioid Peptides/administration & dosage , Opioid Peptides/physiology , Vasodilator Agents/administration & dosage , Nociceptin
8.
Obesity (Silver Spring) ; 16(7): 1510-5, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18421274

ABSTRACT

OBJECTIVE: To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice. METHODS AND PROCEDURES: Male C57BL/6 or Npy5r(-/-) mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r(-/-) mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. RESULTS: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r(-/-) DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. DISCUSSION: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.


Subject(s)
Anti-Obesity Agents/pharmacology , Appetite Depressants/pharmacology , Caloric Restriction , Cyclobutanes/pharmacology , Obesity/drug therapy , Receptors, Neuropeptide Y/antagonists & inhibitors , Spiro Compounds/pharmacology , Spironolactone/pharmacology , Adiposity , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Weight/drug effects , Combined Modality Therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Therapy, Combination , Eating/drug effects , Insulin/blood , Leptin/blood , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/diet therapy , Obesity/metabolism , Obesity/physiopathology , Receptors, Neuropeptide Y/genetics , Receptors, Neuropeptide Y/metabolism , Spironolactone/analogs & derivatives , Time Factors
9.
Mol Pharmacol ; 71(2): 602-8, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17105869

ABSTRACT

Neuropeptide Y (NPY) is thought to have a significant role in the physiological control of energy homeostasis. We recently reported that an NPY Y5 antagonist inhibits body weight gain in diet-induced obese (DIO) mice, with a moderate reduction in food intake. To clarify the mechanism of the antiobesity effects of the Y5 antagonist, we conducted a pair-feeding study in DIO mice. The Y5 antagonist at 100 mg/kg produced a moderate feeding suppression leading to an 18% decrease in body weight, without altering body temperature. In contrast, the pair-fed group showed only a transient weight reduction and a reduced body temperature, thus indicating that the Y5 antagonist stimulates thermogenesis. The Y5 antagonist-treated mice showed an up-regulation of uncoupling protein mRNA in brown adipose tissue (BAT) and white adipose tissue (WAT), suggesting that both BAT and WAT contribute to energy expenditure. Thus, the Y5 antagonist induces its antiobesity effects by acting on both energy intake and expenditure.


Subject(s)
Eating/drug effects , Energy Metabolism/drug effects , Receptors, Neuropeptide Y/antagonists & inhibitors , Weight Loss/drug effects , Adipose Tissue , Animals , Body Temperature , Diet , Energy Intake/drug effects , Ion Channels/genetics , Male , Mice , Mice, Inbred C57BL , Mitochondrial Proteins/genetics , Obesity/drug therapy , Uncoupling Protein 1 , Up-Regulation/drug effects
10.
Proc Natl Acad Sci U S A ; 103(18): 7154-8, 2006 May 02.
Article in English | MEDLINE | ID: mdl-16636293

ABSTRACT

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.


Subject(s)
Anti-Obesity Agents/metabolism , Body Weight , Cyclohexanes/metabolism , Diet , Receptors, Neuropeptide Y/agonists , Receptors, Neuropeptide Y/metabolism , Weight Gain , Xanthenes/metabolism , Adipose Tissue/anatomy & histology , Adipose Tissue/metabolism , Animals , Blood Glucose/metabolism , Cyclohexanes/chemistry , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuropeptide Y , Obesity/genetics , Obesity/metabolism , Organ Size , Rats , Rats, Zucker , Receptors, Neuropeptide Y/genetics , Xanthenes/chemistry
11.
Endocrinology ; 146(7): 3080-6, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15817671

ABSTRACT

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 microg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.


Subject(s)
Diet , Obesity/prevention & control , Obesity/physiopathology , Receptors, Somatostatin/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Administration Schedule , Eating/drug effects , Humans , Hypothalamic Hormones/administration & dosage , Hypothalamic Hormones/pharmacology , Injections, Intraventricular , Male , Melanins/administration & dosage , Melanins/pharmacology , Mice , Mice, Knockout , Motor Activity/drug effects , Obesity/etiology , Pituitary Hormones/administration & dosage , Pituitary Hormones/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/deficiency , Weight Gain/drug effects
12.
J Biol Chem ; 278(47): 46654-60, 2003 Nov 21.
Article in English | MEDLINE | ID: mdl-13129912

ABSTRACT

Obesity is currently considered as an epidemic in the western world, and it represents a major risk factor for life-threatening diseases such as heart attack, stroke, diabetes, and cancer. Taking advantage of DNA microarray technology, we tried to identify the molecules explaining the relationship between obesity and vascular disorders, comparing mRNA expression of about 12,000 genes in white adipose tissue between normal, high fat diet-induced obesity (DIO) and d-Trp34 neuropeptide Y-induced obesity in mice. Expression of monocyte chemoattractant protein-1 (MCP-1) mRNA displayed a 7.2-fold increase in obese mice as compared with normal mice, leading to substantially elevated MCP-1 protein levels in adipocytes. MCP-1 levels in plasma were also increased in DIO mice, and a strong correlation between plasma MCP-1 levels and body weight was identified. We also showed that elevated MCP-1 protein levels in plasma increased the CD11b-positive monocyte/macrophage population in DIO mice. Furthermore, infusion of MCP-1 into lean mice increased the CD11b-positive monocyte population without inducing changes in body weight. Given the importance of MCP-1 in activation of monocytes and subsequent atherosclerotic development, these results suggest a novel role of adiposity in the development of vascular disorders.


Subject(s)
CD11b Antigen/analysis , Chemokine CCL2/physiology , Monocytes/cytology , Obesity/blood , Adipose Tissue/chemistry , Adipose Tissue/metabolism , Animals , Arteriosclerosis/etiology , Chemokine CCL2/blood , Chemokine CCL2/genetics , Gene Expression Profiling , Macrophage Activation , Mice , Mice, Inbred C57BL , Monocytes/immunology , Obesity/complications , RNA, Messenger/analysis
13.
Anal Sci ; 19(7): 1071-3, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12880095

ABSTRACT

For the determination of khellin in urine and serum, fluorometry using HPLC-postcolumn photoirradiation has been developed. Khellin and visnagin of similar structure were separated on a column of Capcell Pak C8. The mobile phase consisted of 40%(v/v) ethanol containing 75 mmol l(-1) H2O2. The postcolumn reagent, 70 mmol l(-1) KH2PO4-NaOH buffer (pH 12.7) containing 50%(v/v) ethanol, were mixed with the mobile phase, which was irradiated with ultraviolet light to induce fluorescence. The fluorescence was monitored with excitation at 378 nm and emission at 480 nm. The calibration graph for khellin was linear over the range of 65 - 2620 ng ml(-1) using an injection volume of 20 microl. The pretreatment of the urine or serum samples consisted of diluting steps or deproteinizing steps using perchloric acid, respectively.


Subject(s)
Chromatography, High Pressure Liquid/methods , Fluorometry/methods , Khellin/blood , Khellin/urine , Calibration , Fluorescence , Humans , Sensitivity and Specificity
14.
Endocrinology ; 144(5): 1793-801, 2003 May.
Article in English | MEDLINE | ID: mdl-12697685

ABSTRACT

To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp(34)NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp(34)NPY (5 and 10 microg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp(34)NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp(34)NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp(34)NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp(34)NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.


Subject(s)
Energy Metabolism , Homeostasis , Obesity/etiology , Obesity/metabolism , Receptors, Neuropeptide Y/physiology , Transcription Factors , Animals , Binding, Competitive , CCAAT-Enhancer-Binding Proteins/genetics , Carrier Proteins/genetics , DNA-Binding Proteins/genetics , Drug Administration Schedule , Glycogen/metabolism , Hyperphagia/etiology , Injections, Intraventricular , Ligands , Lipoprotein Lipase/metabolism , Male , Mice , Mice, Inbred C57BL , Neuropeptide Y/administration & dosage , RNA, Messenger/metabolism , Receptors, Neuropeptide Y/agonists , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Sterol Esterase/metabolism , Sterol Regulatory Element Binding Protein 1 , Triglycerides/metabolism
15.
Am J Physiol Endocrinol Metab ; 284(5): E940-5, 2003 May.
Article in English | MEDLINE | ID: mdl-12554598

ABSTRACT

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitum-fed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.


Subject(s)
Hypothalamic Hormones/administration & dosage , Melanins/administration & dosage , Obesity/chemically induced , Obesity/physiopathology , Pituitary Hormones/administration & dosage , Adipose Tissue/physiopathology , Adipose Tissue, Brown/metabolism , Animals , Body Temperature , Body Weight , Eating , Fatty Acids/metabolism , Injections, Intraventricular , Lipids/biosynthesis , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Organ Size , Oxidation-Reduction , Rectum/physiopathology
16.
Am J Physiol Endocrinol Metab ; 284(3): E583-8, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12453827

ABSTRACT

Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.


Subject(s)
Hypothalamic Hormones/adverse effects , Melanins/adverse effects , Obesity/etiology , Pituitary Hormones/adverse effects , Adipose Tissue/pathology , Animals , Blood Glucose/analysis , Body Weight/drug effects , Dietary Fats/administration & dosage , Drug Administration Schedule , Hyperphagia/chemically induced , Injections, Intraventricular , Insulin/analysis , Leptin/analysis , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Organ Size/drug effects
17.
Br J Pharmacol ; 136(3): 341-6, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12023935

ABSTRACT

1. An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. 2. Oral administration of the Y1 antagonist (30 and 100 mg x kg(-1), once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. 3. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. 4. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity.


Subject(s)
Appetite Depressants/pharmacology , Corticosterone/blood , Morpholines/pharmacology , Obesity/physiopathology , Receptors, Neuropeptide Y/antagonists & inhibitors , Thiazoles/pharmacology , Weight Gain/drug effects , Adipose Tissue/drug effects , Adipose Tissue/pathology , Administration, Oral , Analysis of Variance , Animals , Appetite Depressants/administration & dosage , Cell Size/drug effects , Eating/drug effects , Male , Models, Animal , Obesity/drug therapy , Obesity/metabolism , Rats , Rats, Zucker
SELECTION OF CITATIONS
SEARCH DETAIL
...