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Papers by David York

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999

These experiments were designed to test the hypothesis that the contrasting patterns of macronutr... more These experiments were designed to test the hypothesis that the contrasting patterns of macronutrient selection described previously in AKR/J (fat preference) and SWR/J (carbohydrate preference) mice are not dependent on a single diet paradigm. The effect of mouse strain on proportional fat intake was tested in naive mice by presenting two-choice diets possessing a variety of physical, sensory, and nutritive properties. In three separate experiments, AKR/J mice preferentially selected and consumed a higher proportion of energy from the high-fat diet than SWR/J mice. Specifically, this phenotypic difference was observed with 1) fat-protein vs. carbohydrate-protein diets, independent of fat type (vegetable shortening or lard), 2) isocaloric, high- vs. low-fat liquid diet preparations, and 3) high- vs. low-fat powdered-granular diets. These results confirm our previous observation of a higher proportional fat intake by AKR/J compared with SWR/J mice using the three-choice macronutrient...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998

Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary ... more Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary fat. The selectivity of the response to fat suggests that the rat must recognize a permissive signal related to dietary fat for the Ent biological response. To investigate the nature of this signal, we studied the effects of Ent in rats that were adapted to either a high-fat (HF) or high-carbohydrate/low-fat (HC) diet and then naively exposed to either HF or HC diets. Ent (1 nmol) was injected into the lateral ventricle of overnight-fasted rats, and food intake was measured. Rats adapted to HF diet and tested with HC diet responded to Ent, but rats adapted to HC diet and tested with HF did not respond to Ent. The groups were maintained on their new test diets for up to 21 days and tested again for their response to Ent at 3, 7, 14, and 21 days. Ent response did not appear in HC-adapted rats switched to HF diet before 21 days. Conversely, the HF-adapted rats, which responded to Ent when t...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999

Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT... more Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT) recently was shown to suppress fat and occasionally protein but not carbohydrate intake in rats when a macronutrient selection paradigm was employed. These reports contrast with the prevailing literature, which for the past decade has described a role for serotonin neurotransmission in the modification of dietary carbohydrate consumption. To test the hypothesis that the suppression of fat selection and/or consumption by systemic serotonin agonists involves stimulation of central 5-HT receptors, a series of experiments was performed in nondeprived rats. In experiment 1, third cerebroventricular (3V) infusion of the nonselective 5-HT antagonist metergoline prevented the reduction in fat but not carbohydrate feeding caused by systemic dF. Furthermore, 3V metergoline alone increased fat intake. In experiments 2 and 3, 3V infusion of 5-HT1B/2C receptor agonistsd-norfenfluramine (dNF) or qui...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many form... more Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced cons...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Dietary induced obesity in rodents is associated with a resistance to leptin. We have investigate... more Dietary induced obesity in rodents is associated with a resistance to leptin. We have investigated the hypothesis that dietary fat per se alters the feeding response to peripheral leptin in rats that were fed either their habitual high- or low-fat diet or were naively exposed to the alternative diet. Osborne-Mendel rats were adapted to either high- or low-fat diet. Food-deprived rats were given either leptin (0.5 mg/kg body wt ip) or saline, after which they were provided with either their familiar diet or the alternative diet. Food intake of rats adapted and tested with the low-fat diet was reduced 4 h after leptin injection, whereas rats adapted and tested with a high-fat diet did not respond to leptin. Leptin was injected again 1 and 5 days after the high-fat diet-adapted rats were switched to the low-fat diet. Leptin reduced the food intake on both days. In contrast, when low-fat diet-adapted rats were switched to a high-fat diet, the leptin inhibitory response was present on da...

Physiological Reviews, 1979

International journal of obesity (2005), 2008

We utilized a genomic analysis of the response of neuronal GT1-7 cells to enterostatin to identif... more We utilized a genomic analysis of the response of neuronal GT1-7 cells to enterostatin to identify pathways responsive to this peptide. This information, together with reported properties of the enterostatin receptor, suggested that enterostatin may have an effect on angiogenesis. To investigate this hypothesis, we studied the effect of enterostatin as an antiangiogenic agent in two angiogenic tissue culture model systems. Enterostatin induced a 50% or greater inhibition in the angiogenic response of human fat cells and had a U-shaped bimodal dose-response effect in inhibiting angiogenesis in a human placental vein angiogenesis model. To further understand this response, we tested enterostatin's effect in a human hepatoma cell line (HepG2 cells) that was subjected to glucose deprivation, a condition known to induce angiogenesis in other tumor cell lines. Phosphorylated AMP kinase (pAMPK) levels and vascular endothelial growth factor A (VEGF-A) mRNA expression were elevated robus...

The Journal of nutrition, 2002

Dietary fat and its relation to obesity has been a controversial issue for several years. In this... more Dietary fat and its relation to obesity has been a controversial issue for several years. In this review, several kinds of data relating to this issue are presented. There are epidemiological cross-country data and data within countries showing an effect. However, in the United States, the intake of fat appears to be declining, whereas the prevalence of obesity rises-the American Paradox. Clinical studies show that trans fatty acids can increase insulin resistance and that exercise can enhance the rate of adaptation to a high fat diet by increasing the rate of fat oxidation. The differences in response of inflammatory signals and of insulin resistance to different fatty acids indicate that not all fatty acids are the same. There are also experimental data showing that most, but not all, animals consuming a high fat diet will become obese. A number of mechanisms have been postulated for this difference, including differential sensitivities to neurotransmitters, to the intestinal pept...

Peptides, 2009

Enterostatin is a peptide that regulates dietary fat intake in rodents and inhibits insulin secre... more Enterostatin is a peptide that regulates dietary fat intake in rodents and inhibits insulin secretion from pancreatic beta cells. Microarray studies of the genomic response of both a human hepatoma cell line (HepG2 cells) and a mouse hypothalamic cell line (GT1-7 cells) to enterostatin suggested that it might regulate protein trafficking. Using semi quantitative real-time PCR and western blot analysis, we confirmed that enterostatin upregulated Scamp2 and down regulated Dynamin2 in these cell lines. The receptor for enterostatin is the F 1-ATPase beta subunit. We transfected HepG2 cells with either a Green Fluorescent protein (GFP) tagged F 1-ATPase beta subunit or a Red Fluorescent protein (RFP) tagged F 1-ATPase alpha subunit to study the effects of enterostatin on translocation of its own receptor protein. Enterostatin induced movement of GFP-beta subunit to the cell periphery area but did not have any effect on the localization of RFP-alpha subunit protein in HepG2. As Scamp2 is involved in glucose uptake in mouse Beta-TC6 insulinoma cells we tested enterostatin's effect in Beta-TC6 cells. Glucose stimulated insulin release was inhibited by enterostatin as reported previously. Using siRNA to Scamp2 did not change glucose stimulated insulin release but siRNA to Dynamin2 and dominant negative Dynamin2 (Dyn K44A) inhibited glucose stimulated insulin release and abolished the response to enterostatin. This suggests enterostatin inhibits glucose stimulated insulin release in pancreatic beta cells through down regulation of Dynamin2. This study also suggests that enterostatin might have a more generalized effect on protein trafficking in various cells.

Peptides, 2007

Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, sele... more Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, selectively inhibits fat intake through activation of an afferent vagal signaling pathway. This study investigated if the effects of enterostatin were mediated through a CCKdependent pathway. The series of in vivo and in vitro experiments included studies of 1) the feeding effect of peripheral enterostatin on Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors, 2) the effect of CCK-8S on the intake of a two-choice high-fat (HF)/low-fat (LF) diet, 3) the effects of peripheral or central injection of the CCK-A receptor antagonist lorglumide on the feeding inhibition induced by either central or peripheral enterostatin, and 4) the ability of enterostatin to displace CCK binding in a 3T3 cell line expressing CCK-A receptor gene and in rat brain sections. The results showed that OLTEF rats did not respond to enterostatin (300 g/kg ip) in contrast to the 23% reduction in intake of HF diet in Long Evans Tokushima Otsuka (LETO) control rats. CCK (1 g/kg ip) decreased the intake of the HF diet in a two-choice diet regime with a compensatory increase in intake of the LF diet. Peripheral injection of lorglumide (300 g/kg) blocked the feeding inhibition induced by either near-celiac arterial or intracerebroventricular enterostatin, whereas intracerebroventricular lorglumide (5 nmol icv) only blocked the response to intracerebroventricular enterostatin but not to arterial enterostatin. Enterostatin did not bind on CCK-A receptors because neither enterostatin nor its analogs VPDPR and ␤-casomorphin displaced [ 3 H]L-364,718 from CCK-A receptors expressed in 3T3 cells or the binding of 125 I-CCK-8S from rat brain sections. The data suggest that both the peripheral and central responses to enterostatin are mediated through or dependent on peripheral and central CCK-A receptors.

Obesity, 2007

WHITE, CHRISTY L., YURI ISHIHARA, DAVID A. YORK, AND GEORGE A. BRAY. Effect of metachlorophenylpi... more WHITE, CHRISTY L., YURI ISHIHARA, DAVID A. YORK, AND GEORGE A. BRAY. Effect of metachlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats. Obesity. 2007;15:624-631. Objective: To investigate whether there is a difference in sensitivity to a serotonin agonist, meta-chlorophenylpiperazine (mCPP), or cholecystokinin (CCK-8), an intestinal hormone that inhibits food intake, between the Osborne-Mendel (OM) rat, which becomes obese eating a high-fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietaryinduced obesity. Research Methods and Procedures: OM and S5B rats were adapted to either a high-saturated-fat diet (56% energy as fat) or a low-fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK-8. Results: Treatment with mCPP reduced food intake in both strains of rats. The dose-response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high-fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK-8, there was a similar doserelated suppression of food intake in both the OM and S5B rats. Discussion: These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.

The Journal of Clinical Endocrinology & Metabolism, 1997

Industrial Crops and Products, 2000

Background: Simmondsin is a cyanomethylene glycoside, derived from the desert shrub, Simmondsia c... more Background: Simmondsin is a cyanomethylene glycoside, derived from the desert shrub, Simmondsia chinensis. Simmondsin has been reported to produce weight loss and to decrease food intake, an effect that can be blocked by treatment with an inhibitor of cholecystokinin. Study design: Six experiments were conducted on male Sprague-Dawley rats. Results: In two acute experiments where simmondsin was either added to the diet or injected, there was a dose-related reduction in food intake. The CCK A antagonist, lorglumide, did not block the acute inhibitory effects of simmondsin on food intake and simmondsin did not produce conditioned taste aversion. In two chronic feeding studies, the high dose of simmondsin (0.5%) in the diet produced profound weight loss and death in rats. At autopsy, the kidney, heart and liver of the treated animals were larger than the pair-fed animals and there was a marked suppression of the bone marrow elements with severe anemia. Conclusion: Simmondsin is toxic with profound effects on the hematopoietic system.

Diabetes, 2010

OBJECTIVE The agouti-related protein (Agrp) is a powerful orexigenic peptide, but little is known... more OBJECTIVE The agouti-related protein (Agrp) is a powerful orexigenic peptide, but little is known about its transcriptional regulation. The objective of this study was to determine molecular mechanisms for the activation of hypothalamic Agrp and identify compounds that stimulate appetite. RESEARCH DESIGN AND METHODS We used promoter analyses methods, hypothalamic cell culture and transfection, immunohistochemistry, luciferase-expressing transgenic mice, in vivo bioluminescence, anitisense RNA, mouse feeding studies, indirect calorimetry, real-time PCR, and Western blots. RESULTS We found that the Krüppel-like factor 4 (Klf4) is a potent activator of Agrp by binding to a specific CACCC-box in its minimal promoter. We also found that an extract of tarragon, termed PMI-5011, activated hypothalamic Klf4 and Agrp. In vivo, PMI-5011 increased Agrp promoter activity in luciferase-expressing transgenic mice, increased hypothalamic Klf4 and Agrp expression, increased hypothalamic Orexin and ...

Chinese Medicine, 2007

Background: Chinese herbal extract Number Ten (NT) is a dietary herbal formulation prepared from ... more Background: Chinese herbal extract Number Ten (NT) is a dietary herbal formulation prepared from rhubarb, ginger, astragalus, red sage and tumeric. This study tested the effectiveness of NT in reducing body weight gain in rats. Methods: Sixty female Wistar rats were fed a high fat diet and acclimated to gavage feeding. The rats were divided into five treatment groups: (1) Control (n = 15); (2) NT-H (n = 15), 1.5 g/day; (3) NT-L (n = 10), 0.75 g/day; (4) Pr-fed (n = 10), pair fed to NT-H; (5) d-FF (n = 10), d-fenfluramine 2 mg/kg. Ten rats per group were sacrificed on day 56. Weight, food intake, clinical chemistry and body composition were evaluated. Five animals in the control and 1.5 g/day NT groups were left untreated during a two week recovery period. Results: The 0.75 g/day NT, 1.5 g/day NT, d-fenfluramine and pair fed groups gained 24.6%, 33.3%, 12.3% and 33.3% less than the control respectively (P < 0.0006). Leptin decreased 27.5% to 46.2% in the treatment groups vs. control (P < 0.009). Parametrial fat decreased 14.1% to 55.5% in the NT and pair fed groups vs. control (P < 0.006). The NT groups had soft stools, loss of hair around the mouth and coloration to the urine and stool without evidence of blood or bilirubin (attributed to chromogens in NT). There were no differences between groups in the clinical chemistry. Conclusion: This study demonstrated the efficacy of NT in reducing weight gain in rodents.

Brain Research, 2005

Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has... more Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has been shown to alter 5-HT release in the brain, and non-specific 5-HT antagonists blocked the anorectic response to icv enterostatin. The aim of this study was to further identify which 5-HT receptor subtype mediates the enterostatin feeding behavior and whether this effect occurs due to action in the PVN. Wild-type and 5-HT2C receptor−/− (KO) mice and normal Sprague-Dawley rats were used in these experiments. All animals were fed a high fat diet. Enterostatin (120 nmol, i.p.) reduced the intake of high fat diet in 5-HT2C receptor mutant mice (saline 4.54 ± 0.47 kcal vs. Ent 2.53 ± 0.76 kcal) 1 h after injection. A selective 5-HT1B antagonist (GR55526, 40 mg/kg body weight, i.p.) blocked the enterostatin hypophagic effects in these KO mice. Rats were implanted with cannulas into the amygdala and the ipsilateral PVN. The 5-HT receptor antagonists metergoline (non-specific receptor subtypes 1 and 2), or ritanserin (selective 2C), or GR55562 (selective 1 B) was injected into the PVN prior to enterostatin (0.01 nmol) injection into the amygdala. Enterostatin reduced food intake (saline: 5.80 ± 0.59 g vs. enterostatin 3.47 ± 0.56 g, P < 0.05 at 1 h). Pretreatment with either metergoline (10 nmol) or GR55526 (10 nmol) but not ritanserin (10 nmol) into the PVN attenuated the anorectic response to amygdala enterostatin. The data imply that the enterostatin anorectic response may be modulated by 5-HT1B receptors and that a neuronal pathway from the amygdala to the PVN regulates the enterostatin response through activation of 5-HTlB receptors in PVN.

AJP: Regulatory, Integrative and Comparative Physiology, 2005

Perinatal environment is an important determinant of health status of adults. We tested the hypot... more Perinatal environment is an important determinant of health status of adults. We tested the hypothesis that perinatal ambient temperature alters sympathetic activity and affects body composition in adult life and that this effect differs between S5B/Pl (S5B) and Osborne-Mendel (OM) strains of rat that were resistant (S5B) or susceptible (OM) to dietary obesity. From 1 wk before birth, rat litters were raised at either 18 or 30°C until 2 mo of age while consuming a chow diet. Rats were then housed at normal housing temperature (22°C) and provided either high-fat or low-fat diet. OM rats initially reared at 18°C gained more weight on both diets than those reared at 30°C. Perinatal temperature had no effect on body weight gain of the S5B rats on either diet. At 12 wk of age, OM and S5B rats reared at 18°C had higher intakes of the high-fat diet than those reared at 30°C but lower β3-adrenergic receptor (β3-AR) and uncoupling protein-1 (UCP1) mRNA levels in brown adipose tissue (BAT). T...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2009

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake aft... more The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total cal...

AJP: Endocrinology and Metabolism, 2006

In this study, we investigated the metabolic phenotype of PKCθ knockout mice (C57BL/6J) on chow d... more In this study, we investigated the metabolic phenotype of PKCθ knockout mice (C57BL/6J) on chow diet and high-fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On the chow diet, body weight and food intake were not changed in the KO mice; however, body fat content was increased with a corresponding decrease in body lean mass. Energy expenditure and spontaneous physical activity were decreased in the KO mice. On HFD, energy expenditure and physical activity remained low in the KO mice. The body weight and fat content were increased rapidly in the KO mice. At 8 wk on HFD, severe insulin resistance was detected in the KO mice with hyperinsulinemic euglycemic clamp and insulin tolerance test. Insulin action in both hepatic and peripheral tissues was reduced in the KO mice. Plamsa free fatty acid was increased, and expression of adiponectin in the adipose tissue was decreased, in the KO mice on HFD. This study suggests that loss of PKCθ reduces energy expendit...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999

These experiments were designed to test the hypothesis that the contrasting patterns of macronutr... more These experiments were designed to test the hypothesis that the contrasting patterns of macronutrient selection described previously in AKR/J (fat preference) and SWR/J (carbohydrate preference) mice are not dependent on a single diet paradigm. The effect of mouse strain on proportional fat intake was tested in naive mice by presenting two-choice diets possessing a variety of physical, sensory, and nutritive properties. In three separate experiments, AKR/J mice preferentially selected and consumed a higher proportion of energy from the high-fat diet than SWR/J mice. Specifically, this phenotypic difference was observed with 1) fat-protein vs. carbohydrate-protein diets, independent of fat type (vegetable shortening or lard), 2) isocaloric, high- vs. low-fat liquid diet preparations, and 3) high- vs. low-fat powdered-granular diets. These results confirm our previous observation of a higher proportional fat intake by AKR/J compared with SWR/J mice using the three-choice macronutrient...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998

Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary ... more Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary fat. The selectivity of the response to fat suggests that the rat must recognize a permissive signal related to dietary fat for the Ent biological response. To investigate the nature of this signal, we studied the effects of Ent in rats that were adapted to either a high-fat (HF) or high-carbohydrate/low-fat (HC) diet and then naively exposed to either HF or HC diets. Ent (1 nmol) was injected into the lateral ventricle of overnight-fasted rats, and food intake was measured. Rats adapted to HF diet and tested with HC diet responded to Ent, but rats adapted to HC diet and tested with HF did not respond to Ent. The groups were maintained on their new test diets for up to 21 days and tested again for their response to Ent at 3, 7, 14, and 21 days. Ent response did not appear in HC-adapted rats switched to HF diet before 21 days. Conversely, the HF-adapted rats, which responded to Ent when t...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1999

Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT... more Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT) recently was shown to suppress fat and occasionally protein but not carbohydrate intake in rats when a macronutrient selection paradigm was employed. These reports contrast with the prevailing literature, which for the past decade has described a role for serotonin neurotransmission in the modification of dietary carbohydrate consumption. To test the hypothesis that the suppression of fat selection and/or consumption by systemic serotonin agonists involves stimulation of central 5-HT receptors, a series of experiments was performed in nondeprived rats. In experiment 1, third cerebroventricular (3V) infusion of the nonselective 5-HT antagonist metergoline prevented the reduction in fat but not carbohydrate feeding caused by systemic dF. Furthermore, 3V metergoline alone increased fat intake. In experiments 2 and 3, 3V infusion of 5-HT1B/2C receptor agonistsd-norfenfluramine (dNF) or qui...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many form... more Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced cons...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Dietary induced obesity in rodents is associated with a resistance to leptin. We have investigate... more Dietary induced obesity in rodents is associated with a resistance to leptin. We have investigated the hypothesis that dietary fat per se alters the feeding response to peripheral leptin in rats that were fed either their habitual high- or low-fat diet or were naively exposed to the alternative diet. Osborne-Mendel rats were adapted to either high- or low-fat diet. Food-deprived rats were given either leptin (0.5 mg/kg body wt ip) or saline, after which they were provided with either their familiar diet or the alternative diet. Food intake of rats adapted and tested with the low-fat diet was reduced 4 h after leptin injection, whereas rats adapted and tested with a high-fat diet did not respond to leptin. Leptin was injected again 1 and 5 days after the high-fat diet-adapted rats were switched to the low-fat diet. Leptin reduced the food intake on both days. In contrast, when low-fat diet-adapted rats were switched to a high-fat diet, the leptin inhibitory response was present on da...

Physiological Reviews, 1979

International journal of obesity (2005), 2008

We utilized a genomic analysis of the response of neuronal GT1-7 cells to enterostatin to identif... more We utilized a genomic analysis of the response of neuronal GT1-7 cells to enterostatin to identify pathways responsive to this peptide. This information, together with reported properties of the enterostatin receptor, suggested that enterostatin may have an effect on angiogenesis. To investigate this hypothesis, we studied the effect of enterostatin as an antiangiogenic agent in two angiogenic tissue culture model systems. Enterostatin induced a 50% or greater inhibition in the angiogenic response of human fat cells and had a U-shaped bimodal dose-response effect in inhibiting angiogenesis in a human placental vein angiogenesis model. To further understand this response, we tested enterostatin's effect in a human hepatoma cell line (HepG2 cells) that was subjected to glucose deprivation, a condition known to induce angiogenesis in other tumor cell lines. Phosphorylated AMP kinase (pAMPK) levels and vascular endothelial growth factor A (VEGF-A) mRNA expression were elevated robus...

The Journal of nutrition, 2002

Dietary fat and its relation to obesity has been a controversial issue for several years. In this... more Dietary fat and its relation to obesity has been a controversial issue for several years. In this review, several kinds of data relating to this issue are presented. There are epidemiological cross-country data and data within countries showing an effect. However, in the United States, the intake of fat appears to be declining, whereas the prevalence of obesity rises-the American Paradox. Clinical studies show that trans fatty acids can increase insulin resistance and that exercise can enhance the rate of adaptation to a high fat diet by increasing the rate of fat oxidation. The differences in response of inflammatory signals and of insulin resistance to different fatty acids indicate that not all fatty acids are the same. There are also experimental data showing that most, but not all, animals consuming a high fat diet will become obese. A number of mechanisms have been postulated for this difference, including differential sensitivities to neurotransmitters, to the intestinal pept...

Peptides, 2009

Enterostatin is a peptide that regulates dietary fat intake in rodents and inhibits insulin secre... more Enterostatin is a peptide that regulates dietary fat intake in rodents and inhibits insulin secretion from pancreatic beta cells. Microarray studies of the genomic response of both a human hepatoma cell line (HepG2 cells) and a mouse hypothalamic cell line (GT1-7 cells) to enterostatin suggested that it might regulate protein trafficking. Using semi quantitative real-time PCR and western blot analysis, we confirmed that enterostatin upregulated Scamp2 and down regulated Dynamin2 in these cell lines. The receptor for enterostatin is the F 1-ATPase beta subunit. We transfected HepG2 cells with either a Green Fluorescent protein (GFP) tagged F 1-ATPase beta subunit or a Red Fluorescent protein (RFP) tagged F 1-ATPase alpha subunit to study the effects of enterostatin on translocation of its own receptor protein. Enterostatin induced movement of GFP-beta subunit to the cell periphery area but did not have any effect on the localization of RFP-alpha subunit protein in HepG2. As Scamp2 is involved in glucose uptake in mouse Beta-TC6 insulinoma cells we tested enterostatin's effect in Beta-TC6 cells. Glucose stimulated insulin release was inhibited by enterostatin as reported previously. Using siRNA to Scamp2 did not change glucose stimulated insulin release but siRNA to Dynamin2 and dominant negative Dynamin2 (Dyn K44A) inhibited glucose stimulated insulin release and abolished the response to enterostatin. This suggests enterostatin inhibits glucose stimulated insulin release in pancreatic beta cells through down regulation of Dynamin2. This study also suggests that enterostatin might have a more generalized effect on protein trafficking in various cells.

Peptides, 2007

Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, sele... more Enterostatin, a pentapeptide released from the exocrine pancreas and gastrointestinal tract, selectively inhibits fat intake through activation of an afferent vagal signaling pathway. This study investigated if the effects of enterostatin were mediated through a CCKdependent pathway. The series of in vivo and in vitro experiments included studies of 1) the feeding effect of peripheral enterostatin on Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors, 2) the effect of CCK-8S on the intake of a two-choice high-fat (HF)/low-fat (LF) diet, 3) the effects of peripheral or central injection of the CCK-A receptor antagonist lorglumide on the feeding inhibition induced by either central or peripheral enterostatin, and 4) the ability of enterostatin to displace CCK binding in a 3T3 cell line expressing CCK-A receptor gene and in rat brain sections. The results showed that OLTEF rats did not respond to enterostatin (300 g/kg ip) in contrast to the 23% reduction in intake of HF diet in Long Evans Tokushima Otsuka (LETO) control rats. CCK (1 g/kg ip) decreased the intake of the HF diet in a two-choice diet regime with a compensatory increase in intake of the LF diet. Peripheral injection of lorglumide (300 g/kg) blocked the feeding inhibition induced by either near-celiac arterial or intracerebroventricular enterostatin, whereas intracerebroventricular lorglumide (5 nmol icv) only blocked the response to intracerebroventricular enterostatin but not to arterial enterostatin. Enterostatin did not bind on CCK-A receptors because neither enterostatin nor its analogs VPDPR and ␤-casomorphin displaced [ 3 H]L-364,718 from CCK-A receptors expressed in 3T3 cells or the binding of 125 I-CCK-8S from rat brain sections. The data suggest that both the peripheral and central responses to enterostatin are mediated through or dependent on peripheral and central CCK-A receptors.

Obesity, 2007

WHITE, CHRISTY L., YURI ISHIHARA, DAVID A. YORK, AND GEORGE A. BRAY. Effect of metachlorophenylpi... more WHITE, CHRISTY L., YURI ISHIHARA, DAVID A. YORK, AND GEORGE A. BRAY. Effect of metachlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats. Obesity. 2007;15:624-631. Objective: To investigate whether there is a difference in sensitivity to a serotonin agonist, meta-chlorophenylpiperazine (mCPP), or cholecystokinin (CCK-8), an intestinal hormone that inhibits food intake, between the Osborne-Mendel (OM) rat, which becomes obese eating a high-fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietaryinduced obesity. Research Methods and Procedures: OM and S5B rats were adapted to either a high-saturated-fat diet (56% energy as fat) or a low-fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK-8. Results: Treatment with mCPP reduced food intake in both strains of rats. The dose-response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high-fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK-8, there was a similar doserelated suppression of food intake in both the OM and S5B rats. Discussion: These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.

The Journal of Clinical Endocrinology & Metabolism, 1997

Industrial Crops and Products, 2000

Background: Simmondsin is a cyanomethylene glycoside, derived from the desert shrub, Simmondsia c... more Background: Simmondsin is a cyanomethylene glycoside, derived from the desert shrub, Simmondsia chinensis. Simmondsin has been reported to produce weight loss and to decrease food intake, an effect that can be blocked by treatment with an inhibitor of cholecystokinin. Study design: Six experiments were conducted on male Sprague-Dawley rats. Results: In two acute experiments where simmondsin was either added to the diet or injected, there was a dose-related reduction in food intake. The CCK A antagonist, lorglumide, did not block the acute inhibitory effects of simmondsin on food intake and simmondsin did not produce conditioned taste aversion. In two chronic feeding studies, the high dose of simmondsin (0.5%) in the diet produced profound weight loss and death in rats. At autopsy, the kidney, heart and liver of the treated animals were larger than the pair-fed animals and there was a marked suppression of the bone marrow elements with severe anemia. Conclusion: Simmondsin is toxic with profound effects on the hematopoietic system.

Diabetes, 2010

OBJECTIVE The agouti-related protein (Agrp) is a powerful orexigenic peptide, but little is known... more OBJECTIVE The agouti-related protein (Agrp) is a powerful orexigenic peptide, but little is known about its transcriptional regulation. The objective of this study was to determine molecular mechanisms for the activation of hypothalamic Agrp and identify compounds that stimulate appetite. RESEARCH DESIGN AND METHODS We used promoter analyses methods, hypothalamic cell culture and transfection, immunohistochemistry, luciferase-expressing transgenic mice, in vivo bioluminescence, anitisense RNA, mouse feeding studies, indirect calorimetry, real-time PCR, and Western blots. RESULTS We found that the Krüppel-like factor 4 (Klf4) is a potent activator of Agrp by binding to a specific CACCC-box in its minimal promoter. We also found that an extract of tarragon, termed PMI-5011, activated hypothalamic Klf4 and Agrp. In vivo, PMI-5011 increased Agrp promoter activity in luciferase-expressing transgenic mice, increased hypothalamic Klf4 and Agrp expression, increased hypothalamic Orexin and ...

Chinese Medicine, 2007

Background: Chinese herbal extract Number Ten (NT) is a dietary herbal formulation prepared from ... more Background: Chinese herbal extract Number Ten (NT) is a dietary herbal formulation prepared from rhubarb, ginger, astragalus, red sage and tumeric. This study tested the effectiveness of NT in reducing body weight gain in rats. Methods: Sixty female Wistar rats were fed a high fat diet and acclimated to gavage feeding. The rats were divided into five treatment groups: (1) Control (n = 15); (2) NT-H (n = 15), 1.5 g/day; (3) NT-L (n = 10), 0.75 g/day; (4) Pr-fed (n = 10), pair fed to NT-H; (5) d-FF (n = 10), d-fenfluramine 2 mg/kg. Ten rats per group were sacrificed on day 56. Weight, food intake, clinical chemistry and body composition were evaluated. Five animals in the control and 1.5 g/day NT groups were left untreated during a two week recovery period. Results: The 0.75 g/day NT, 1.5 g/day NT, d-fenfluramine and pair fed groups gained 24.6%, 33.3%, 12.3% and 33.3% less than the control respectively (P < 0.0006). Leptin decreased 27.5% to 46.2% in the treatment groups vs. control (P < 0.009). Parametrial fat decreased 14.1% to 55.5% in the NT and pair fed groups vs. control (P < 0.006). The NT groups had soft stools, loss of hair around the mouth and coloration to the urine and stool without evidence of blood or bilirubin (attributed to chromogens in NT). There were no differences between groups in the clinical chemistry. Conclusion: This study demonstrated the efficacy of NT in reducing weight gain in rodents.

Brain Research, 2005

Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has... more Serotonin (5-HT) is considered to play an important role in control of appetite. Enterostatin has been shown to alter 5-HT release in the brain, and non-specific 5-HT antagonists blocked the anorectic response to icv enterostatin. The aim of this study was to further identify which 5-HT receptor subtype mediates the enterostatin feeding behavior and whether this effect occurs due to action in the PVN. Wild-type and 5-HT2C receptor−/− (KO) mice and normal Sprague-Dawley rats were used in these experiments. All animals were fed a high fat diet. Enterostatin (120 nmol, i.p.) reduced the intake of high fat diet in 5-HT2C receptor mutant mice (saline 4.54 ± 0.47 kcal vs. Ent 2.53 ± 0.76 kcal) 1 h after injection. A selective 5-HT1B antagonist (GR55526, 40 mg/kg body weight, i.p.) blocked the enterostatin hypophagic effects in these KO mice. Rats were implanted with cannulas into the amygdala and the ipsilateral PVN. The 5-HT receptor antagonists metergoline (non-specific receptor subtypes 1 and 2), or ritanserin (selective 2C), or GR55562 (selective 1 B) was injected into the PVN prior to enterostatin (0.01 nmol) injection into the amygdala. Enterostatin reduced food intake (saline: 5.80 ± 0.59 g vs. enterostatin 3.47 ± 0.56 g, P < 0.05 at 1 h). Pretreatment with either metergoline (10 nmol) or GR55526 (10 nmol) but not ritanserin (10 nmol) into the PVN attenuated the anorectic response to amygdala enterostatin. The data imply that the enterostatin anorectic response may be modulated by 5-HT1B receptors and that a neuronal pathway from the amygdala to the PVN regulates the enterostatin response through activation of 5-HTlB receptors in PVN.

AJP: Regulatory, Integrative and Comparative Physiology, 2005

Perinatal environment is an important determinant of health status of adults. We tested the hypot... more Perinatal environment is an important determinant of health status of adults. We tested the hypothesis that perinatal ambient temperature alters sympathetic activity and affects body composition in adult life and that this effect differs between S5B/Pl (S5B) and Osborne-Mendel (OM) strains of rat that were resistant (S5B) or susceptible (OM) to dietary obesity. From 1 wk before birth, rat litters were raised at either 18 or 30°C until 2 mo of age while consuming a chow diet. Rats were then housed at normal housing temperature (22°C) and provided either high-fat or low-fat diet. OM rats initially reared at 18°C gained more weight on both diets than those reared at 30°C. Perinatal temperature had no effect on body weight gain of the S5B rats on either diet. At 12 wk of age, OM and S5B rats reared at 18°C had higher intakes of the high-fat diet than those reared at 30°C but lower β3-adrenergic receptor (β3-AR) and uncoupling protein-1 (UCP1) mRNA levels in brown adipose tissue (BAT). T...

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2009

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake aft... more The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total cal...

AJP: Endocrinology and Metabolism, 2006

In this study, we investigated the metabolic phenotype of PKCθ knockout mice (C57BL/6J) on chow d... more In this study, we investigated the metabolic phenotype of PKCθ knockout mice (C57BL/6J) on chow diet and high-fat diet (HFD). The knockout (KO) mice are normal in growth and reproduction. On the chow diet, body weight and food intake were not changed in the KO mice; however, body fat content was increased with a corresponding decrease in body lean mass. Energy expenditure and spontaneous physical activity were decreased in the KO mice. On HFD, energy expenditure and physical activity remained low in the KO mice. The body weight and fat content were increased rapidly in the KO mice. At 8 wk on HFD, severe insulin resistance was detected in the KO mice with hyperinsulinemic euglycemic clamp and insulin tolerance test. Insulin action in both hepatic and peripheral tissues was reduced in the KO mice. Plamsa free fatty acid was increased, and expression of adiponectin in the adipose tissue was decreased, in the KO mice on HFD. This study suggests that loss of PKCθ reduces energy expendit...