Progress 07/16/13 to 09/30/17
Outputs
Target Audience:The primary target audience for this project were other researchers that study natural products for the management of obesity and body weight. In addition, our secondary target audience were devlopmental researchers that study the consequences of an obesogenic environment. Our research would also have an appeal to indivduals that had a general interest in understanding how the periphery and central nervous system controls feeding behavior using natural products and dietary supplements. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Work on this project was conducted by undergraduate and graduate students. These students receive in vivo training on how to investigate whether a dietary supplemnt or natural product influences feeding behavior and metabolic outcomes in obese mice. Specifically, they will learn how to perform glucose and insulin tolerance tests, conditioned taste aversion tests, two-bottle preference, and record hemodynamic measures and feeding behaviors. Students will also receive training in gene expression, immunohistochemistry, and electrophysiological techniques. Our ongoing studies will give them training on data acquisition, analysis, and presentation of their findings. Data will be presented by the students at conferences of regional, national, and international professional societies. Students will contribute writing of their research findings for submission of peer-reviewed publications. How have the results been disseminated to communities of interest?For the scientific and genral public audiences, our findings were presented as posters at several open scientifc forums. Our findings were also presented at the 10th Annual Pioneers in Endocrinology Workshop at Rutgers, which was attended by the other researchers, undergraduate students, and the general public.We are in the process of reporting our findings in a peer-reveiwed publication. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Raspberry ketone(4-(4-hydroxyphenyl)-2-butanone) is a popular dietary supplement marketed in United States for weight loss. There is, however, little evidence on the effectiveness of this compound. Our project investigated the antiobesity signature of raspberry ketone in diet-induced obese mice. Specifically, we examined the preventative action of raspberry ketone on the central and peripheral factors involved in body weight homeostasis.The findings from this preclinical research will provide an understanding how raspberry ketone prevents weight gain and retains metabolic control in face of an environment that promotes obesity and overeating. Red raspberries (Rubus idaeus) contain a large number of unexplored other polyphenolic compounds. We investigated whether a purified phenolic-enriched raspberry extract would reduce weight gain in a diet-induced obese (DIO) mouse model. For comparison, we used raspberry ketone as a positive control. Male 8 week-old C57BL/6 mice were used at the start of the study and fed high-fat diet (45% fat. 20% protein). Vehicle, raspberry ketone, high and low raspberry extract (REH 2g/kg, REL 0.2mg/kg, respectively) were administered by oral gavage for 24 days, and body weights were recorded daily. By the end of the dosing period, the RK mice weighed less than the vehicle. For the oral glucose tolerance test, at 15 minutes RK and REH had lower blood glucose compared to vehicle. A separate non-obese group of mice, fed normal chow, underwent glucose tolerance tests with a pretreatment of above doses 60 minutes prior to administration of glucose bolus (2g/kg). Blood glucose at 15, 30 and 60 minutes and area under the curve (AUC), for REH pretreated group was higher than all other groups. Hemodynamic effects were also noted as a consequence of the RK and RE. Hormone and hypothalamic gene expression differences were also noted in these groups compared with the vehicle-treated group. These studies are in the process of being prepared for submission to peer-reviewed publication.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Gotthardt JL and Bello NT. Meal pattern alterations associated with intermittent fasting for weight loss are normalized after high-fat diet re-feeding. Physiology & Behavior. Volume 174, 15 May 2017, Pages 49-56.
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Bello NT and Yeomans BL.Safety of pharmacotherapy options for bulimia nervosa and binge eating disorder. Expert Opin Drug Saf. 2017 Oct 31:1-7.
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Progress 10/01/15 to 09/30/16
Outputs
Target Audience:The target audiences for this project are researchers and the general public that use phytochemicals and botanical supplements. Specifically our findings would be of interest for individuals using natural chemicals for weight loss and improved metabolic health. Ultimately our data would provide critical information for uncovering the physiological and neural mechanisms of a popular natural product used for weight loss. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Two undergraduate students and one graduate student assisted with this project. Under my supervision, the students involved in this project were instructed on several in vivo techniques used in feeding behaviors studies. Students learned how to handle and gavage mice, record food intake, use the Echo MRI to measure fat mass, and measure hemodynamic outcomes. Undergraduate students also completed a written report on their involvement in the project and presented their results as a poster in undergraduate research forum at Rutgers. Throughout this process I interacted with the students to provide them with critical feedback on their performance in the lab, written papers, and poster preparations and presentations. Professional development training for undergraduate and graduate students included how to conduct hands-on in vivo research, science writing, career mentoring, and communication skills. How have the results been disseminated to communities of interest?In May 2016, an undergraduate presented his interim research findings examining the neural activation of raspberry ketone in at the 12th annual Aresty Undergraduate Research Symposium. In September 2016, at a public forum at Rutgers, The State University of New Jersey, another undergraduate student presented a poster on raspberry ketone. This presentation included current findings and proposed research project with raspberry ketone. What do you plan to do during the next reporting period to accomplish the goals?In addition, to preparing the raspberry ketone finding for peer-reviewed publication, our next reporting period we are examining the preventative actions of Rubus idaeus extracts on the metabolic outcomes of diet-induced obesity. Based on the limited in vivo and in vitro studies using raspberry extracts, our hypothesis is that long-term treatment with a R. idaeus extract reduces the metabolic signature associated with diet-induced obesity. Preparation of our phenolic enriched extract will be standardized for raspberry ketone. We will also test the hypothesis that the R. idaeus extract is superior to raspberry ketone in obesity-related metabolic alterations. Our first set of experiments will uncover the mechanism(s) of excessive weight gain prevention associated with enriched R. idaeus extracts. We will use male mice to examine the long-term preventative effects of R. idaeus extracts on body weight homeostasis. This will include measuring (i) caloric intake and meal patterns, (ii) expression of gastrointestinal and hypothalamic feeding-related signals, and (iii) circulating hormones and cytokines. Our hypothesis is that R. idaeus extracts enhances the integration of the peripheral and central signaling pathways that control excessive weight gain. For our second set of experiments will examine the metabolic improvement associated with enriched R.idaeus extracts. We will use male mice to examine the long-term preventative effects of R. idaeus extracts on metabolic outcomes. This will include measuring (i) hemodynamic parameters (ii) body composition and (iii) glucose regulation. Our hypothesis is that R. idaeus extracts prevent excessive weight gain by correcting the metabolic imbalance associated with obesity. The long-term goal of our studies is to validate and identify the metabolic signature of R. idaeus extracts on obesity-related outcomes. Future projects will utilize both in vivo and in vitro techniques to determine the bioaccesibility/bioavailability of R. idaeus whole fruit extracts.
Impacts
What was accomplished under these goals?
Several exogenously administered gastrointestinal peptides or analogues, such as CCK and GLP-1, produce reductions in food intake and a conditioned taste aversion. With this in mind, we addressed the question of whether raspberry ketone activates hindbrain feeding pathways by measuring neural activation following an acute oral dose of raspberry ketone (200 mg/kg) or vehicle in non-obese male C57BL/6 mice (n = 10). Neural activation was performed by using immunohistochemistry of the immediate early gene, c-Fos. We found that oral dosing of raspberry ketone significantly increased (t = 6.3, p < 0.005) the number of immunopositive cells in the caudal hindbrain structure, nucleus of the solitary tract (NTS). There was no significant activation of hypothalamic nuclei. We concluded from this experiment that raspberry ketone activates hindbrain neural pathways involved in feeding. This activation is likely via vagal-mediated pathways. To investigate whether raspberry ketone would be effective to reduce food intake in obese animals, male C57/Bl6 mice were fed high-fat diet (45% fat, 20% protein; D12451, Research Diets, New Brunswick, NJ) for 4 weeks. To accurately determine effects of repeated oral dosing on intake on meal patterns and cumulative intake, mice were placed in the BioDAQ system (Research Diets, New Brunswick, NJ), which is comprehensive food intake monitoring system that can continuously measure food intake and meal patterns, including size, duration and frequency. Mice received a daily oral gavage of raspberry ketone (200 mg/kg; n = 7) or vehicle (n = 7) for 7 days, while meal patterns were recorded. We found raspberry ketone reduced cumulative caloric intake of high-fat diet over the 7-day treatment [F(1, 12) = 5.3, p < 0.05]. We concluded from that repeated dosing of raspberry ketone reduces high-fat diet intake in diet-induced obese animals.
Publications
- Type:
Book Chapters
Status:
Published
Year Published:
2016
Citation:
Zahner MR, Bello NT. Chapter 1 - Central Nervous System Stimulants and Drugs That Suppress Appetite. Side Effects of Drugs Annual. Volume 38, Pages 1-562 (2016) A Worldwide Yearly Survey of New Data in Adverse Drug Reactions Edited by Sidhartha D. Ray. ISBN: 978-0-444-63718-5
- Type:
Journal Articles
Status:
Accepted
Year Published:
2016
Citation:
Gotthardt JD, Bello NT. Can we win the war on obesity with pharmacotherapy? Expert Rev Clin Pharmacol. 2016 Sep 13:1-9. [Epub ahead of print]
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Progress 10/01/14 to 09/30/15
Outputs
Target Audience:The target audiences for this project are researchers and the general public that use phytochemicals and botanical supplements. Specifically our findings would be of interest for individuals using natural chemicals for weight loss and improved metabolic health. Ultimately our data would provide critical information for uncovering the physiological and neural mechanisms of a popular natural product used for weight loss. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Current work on the project is being conducted by an undergraduate student and graduate student. A former undergraduate student also worked on this project and presented his data in a research forum. These students receive in vivo training on how to investigate whether a bioactive phenolic compound influences feeding behavior and metabolic outcomes in non-obese and obese mice. Specifically, they will learn how to perform glucose and insulin tolerance tests, conditioned taste aversion tests, two-bottle preference, and record hemodynamic measures and automated feeding behaviors. Students will also receive training in gene expression and immunohistochemistry techniques. Our current and proposed will studies will give them training on data acquisition, analysis, and presentation of their findings. Data will be presented by the students at conferences of regional, national, and international professional societies. Students will contribute writing of their research findings for submission of peer-reviewed publications. How have the results been disseminated to communities of interest?In May 2015, an undergraduate presented his interim research findings examining the neural activation of raspberry ketone in at the 11th annual Aresty Undergraduate Research Symposium. This student received honorable mention in the STEM field (https://aresty.rutgers.edu/about-aresty/spotlight/2015-best-poster-winners-announced). In September 2015, at a public forum at Rutgers, The State University of New Jersey, another undergraduate student presented her honors thesis proposal. This presentation included current findings and proposed research project with raspberry ketone. What do you plan to do during the next reporting period to accomplish the goals?Previous studies using raspberry ketone have demonstrated acute feeding suppression and engagement of feeding-related hindbrain structures. Over the next year we will examine the preventative effects of raspberry ketone on the neural and metabolic outcomes of diet-induced obesity in mice. Because raspberry ketone bears structural resemblance to synephrine and ephedrine, two compounds with known cardiovascular adverse effects, we will examine the impact of raspberry ketone on hemodynamic outcomes. Also, we will compare the beneficial effects of raspberry ketone with that of a phenolic-enriched whole fruit red raspberry extract. In addition, we will continue our ongoing projects examining the feeding- and stress- related behaviors of Citrus aurantium and Rhodiola rosea extracts.
Impacts
What was accomplished under these goals?
Red raspberries (Rubus idaeus) whole fruit extracts have been shown to have preventative effects for several diseases, such as cardiovascular impairments and hepatic cancers. A ketone [4-(4-hydroxyphenyl)-2-butanone] derived from R. idaeus and has purported antiobesity properties. Despite the popular press coverage of this proclaimed "miracle fat burner in a bottle" and huge internet sales, the safety, efficacy, and mechanism of action of raspberry ketone as a weight loss supplement are still unclear. While several studies have demonstrated lipolytic activity for raspberry ketone in vitro, there are only two in vivo studies in rodents that have examined the ability of raspberry ketone to prevent obesity and reduce dyslipidemia. The purpose of these set of experiments was to determine whether raspberry ketone suppressing feeding behavior and whether the compound activates feeding-related neural pathways. To investigate the feeding suppressive effects of raspberry ketone, raspberry ketone was purchased from an online source. The verification of this raspberry ketone was performed by LC/UV/MS. Non-obese adult male mice C57/BL6 (approximately 30g; n=10) were maintained on standard chow (Purina 5001; 23% protein, 4.5% fat; 3.36 Kcal/g). Because compounds that promote feeding suppression could be doing so by gastrointestinal (GI) illness, we examined the intake of kaolin in rodents. Kaolin has been used as a metric for assessing GI illness in rodents. As such, mice had exposure to kaolin during food intake measurements. Immediately following the gavage, animals were refed and food intake measured at 0.5, 1, 4, 24 h post-gavage. Chow, kaolin, and spillage were measured to the nearest 0.01g. Doses of vehicle and raspberry ketone were separated by one week. Food and kaolin intake were analyzed by separate ANOVA with repeated measures with Newman-Keuls post-hoc testing. Post-hoc testing revealed that raspberry ketone suppressed food intake, compared with vehicle, at all measured time points (p < 0.05 for all). There was no difference in kaolin intake between raspberry ketone doses and vehicle. In order to determine whether raspberry ketone act on the central controls of feeding, we examined the neural activation by c-Fos immunoreactivity following acute dosing. Two brain regions we focused on were the hindbrain and hypothalamic structures. Data are forthcoming and will be submitted for a peer-reviewed publication.
Publications
- Type:
Theses/Dissertations
Status:
Submitted
Year Published:
2015
Citation:
Undergraduate Honor Thesis: "Effects of raspberry ketone (4(4-hydroxyphenyl)-2-butanone on metabolic outcomes in diet-induced obese mice"
- Type:
Other
Status:
Accepted
Year Published:
2015
Citation:
Poster title: "Raspberry Ketone Effects on Feeding and Neural Activation". Honorable mention in undergraduate research forum (https://aresty.rutgers.edu/about-aresty/spotlight/2015-best-poster-winners-announced)
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Progress 10/01/13 to 09/30/14
Outputs
Target Audience: For this funding period, our target audience were the local and academic communities in NJ, and fellow researchers. This included scientific and non-scientific audiences interested in natural products for weight loss. Undergraduate students presented data in a poster format at a research forum that was open to the public and was attended by fellow researchers at Rutgers. I also presented findings from this project in oral presntation (20 min) at the 4th Annual Symposium on the Preventation of Metabolic Syndrome by Dietary Phytochemicals on October 10th, 2013 at Penn State University, University Park, PA. This was attended by scientific researchers. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? Three undergraduate students and one graduate student assisted with this project. Under my supervision, the students involved in this project were instructed on several in vivo techniques used in feeding behaviors studies. Students learned how to handle and gavage mice, record food intake, use the Echo MRI to measure fat mass, and measure hemodynamic outcomes. Undergraduate students also completed a written report on their involvement in the project and presented their results as a poster in undergraduate research forum at Rutgers. Throughout this process I interacted with the students to provide them with critical feedback on their performance in the lab, written papers, and poster preparations and presentations. Professional development training for undergraduate and graduate students included how to conduct hands-on in vivo research, science writing, career mentoring, and communication skills. How have the results been disseminated to communities of interest? Interim results from this project were presented at the Aresty Undergraduate research forum. This research forum is open to public and members of the local press are in attendance. I also presented findings at the 4th Annual Symposium on the Preventation of Metabolic Syndrome by Dietary Phytochemicals. What do you plan to do during the next reporting period to accomplish the goals? It appears there are acute appetitive effects of C. aurantium + R. rosea on feeding suppression in standard chow. Data collected in rats indicate that this was not a result from gastric intestinal disturbances (Verpeut et al. 2013). As a result, we are planning to examine the effects of C. aurantium and R. rosea alone or in combination on meal patterns using the BioDAQ system (Research Diets, New Brunswick, NJ). This will give us an assessment of how C. aurantium and R. rosea interact to reduce food intake. In addition, we will examine whether these botanicals activate hindbrain neural pathways involved in the meal size. For this we will perform immunehistochemistry of c-Fos, an immediate early gene used as a marker for neural activation, following oral dosing of C. auarantium and R. rosea alone or in combination. Another aspect of the interaction of C. aurantium and R. rosea, will be to examine the metabolic effects. To do this, we will measure vO2, vCO2, RER (respiratory exchange ratio or energy expenditure, vCO2/vCO2), heat, and locomotor activity by indirect calorimeter using a Comprehensive Lab Animal Monitoring System (CLAMS; Columbus Instruments, Columbus, OH). Using the same approach for determining the anti-obesity effects of C. aurantium and R. rosea, we have also begun to examine the antiobesity effects of raspberry ketone (4-(4-hydroxyphenyl) 2-butanone). Raspberry ketone is an FDA-designated GRAS additive, derived for the fruit of the red raspberry (Rubus idaeus), and has been purported to possess antiobesity properties. Despite the popular press coverage of this "miracle fat burner in a bottle" and huge internet sales, there are only two in vivo studies examining the obesity-preventative and dyslipidemia-reducing effects in rodents. Raspberry ketone also has been shown to increase lipolysis and fat oxidation in vitro. Nonetheless, no study has systematically tested whether raspberry ketone improves the meal pattern, metabolic rate, taste sensitivity, hypothalamic genes expression, glucose homeostasis, and cardiovascular alterations associated with obesity. Raspberry ketone was acquired from Raspberry Ketone Premium (Norcross, GA), which is an FDA registered facility and has provided us with certificate of analysis. Verification of raspberry ketone and the presence of any microbial contaminants in accordance with NIH guidelines for botanical sources compounds were conducted by HPLC analysis in the Simon/Wu laboratory at Rutgers. Adult diet-induced obese male mice (C57BL/6; >12 weeks high-fat diet) will receive vehicle (10% DMSO), 50, 100, 200 mg/kg/day or a reduced calorie low-fat diet (positive control). Treatments by oral gavage or diet access will be > 4 weeks. The findings from these experiments will provide mechanistic data on the anti-obesity effects of raspberry ketone. By conducting these experiments together, this will allow us to compare anti-obesity outcomes between raspberry ketone and C. aurantium + R. rosea.
Impacts
What was accomplished under these goals?
This project examines the anti-obesity potential of two botanicals extracts, C. aurantium (Bitter Orange) and R. rosea (Artic Root), in mice. First, we sought to determine the dose response of C. aurantium and R. rosea alone or in combination on acute food intake feeding suppression. Adult male mice (C57/BL6; Jackson Laboratories; N=18) fed standard chow (Purina 5001; 4.5% Fat; 23% protein) were used for this study. One group received C. aurantium (2% ethanol: 5.6, 10, or 20 mg/kg), another group received R. rosea (2% ethanol: 6.4, 20, or 40 mg/kg), and a third group received C. aurantium (5.6, 10, or 20 mg/kg) + R. rosea (6.4, 20, or 40 mg/kg). For C. aurantium + R rosea dosing, the vehicle was 2% ethanol. Food intake measurements were recorded at 4 and 24 hours post oral gavage. Results indicate the C. aurantium (20 mg/kg) + R. rosea (40 mg/kg) produced a significant reduction in the 4-hour food intake of mice compared to mice receiving just C. aurantium (40 mg/kg; p < 0.05). Second, we sought to determine whether long-term dosing of C. aurantium and R. rosea alone or in combination reduced body weight and adiposity in diet-induced obese mice. Adult male mice (C57/BL6; Jackson Laboratories; N = 18) were fed high-fat diet (Research Diets; 45% Fat; 20% protein, N = 46) or low fat diet (Research Diets; 10% Fat, 20% protein, N = 8) were used for this study. Animals on the low-fat diet were used as positive controls. After 12 weeks, mice on the high-fat diet were split into groups to receive one of four oral gavage treatments. One group received C. aurantium (20 mg/kg), the second group received R. rosea (40 mg/kg), and the third group received C.aurantium (20 mg/kg) + R. rosea (40 mg/kg). A fourth group was a vehicle groups and received 2% ethanol. Animals were oral gavaged once daily with respective treatments for 14 consecutive days. Two days prior to beginning the treatments all mice were put through an EchoMRI-130 body composition analyzer to determine the amount of fat and lean mass. After 7 days and 14 days of treatment all mice (including the low-fat diet fed group) were run through the Echo MRI analyzer. At the completion of the 14 days treatments, hemodynamic measures were determined by a non-invasive tail volume-pressure recording system (CODA, Kent Scientific). Obese mice receiving C. aurantium, R. rosea, C. aurantium + R. rosea, or vehicle did not differ in body weight of fat mass. Animals on the low-fat diet did have reductions in body weight and fat mass compared with all the treatment groups (p < 0.05 for all). Hemodynamic measurements were not different between groups
Publications
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2013
Citation:
Bello, N.2013 A cold and bitter treatment for obesity? Antiobesity effects of Rhodiola rosea (arctic root) and Citrus aurantium (bitter orange). 4th Annual Symposium on the Prevention of Metabolic Syndrome by Dietary Phytochemicals, Penn State University, University Park, PA
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Progress 07/16/13 to 09/30/13
Outputs
Target Audience:
Nothing Reported
Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
This project examines the anti-obesity potential of two botanicals, Citrus aurantium (Bitter Orange) and Rhodiola rosea (Artic Root), in mice. our prior researchdemonstrated that these two botanicals interact to reduce standard chow food intake and decrease white adipose tissue weight in male Sprague Dawley rats fed a high fat diet for 13 weeks. During this reporting period, we examined what combinational doses of the botanicals Citrus aurantium and Rhodiola rosea reduced food intake in mice (C57BL/6). What we found is the combined use of 20 mg/kg of C. aurantium and 40 mg/kg R. rosea produced an approximate 10% reduction in standard chow food intake. Because we have observed similar difference in rats, these findings in mice support the anti-obesity effects of this botanical combination. These initial findings will provide a basis for uncovering the physiological mechanisms of the interaction between C. aurantium and R. rosea.
Publications
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