scholarly journals SAT-607 The Vagus Nerve and the Hypothalamus Mediate Different Aspects of the Anorectic Effects of PYY3-36

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aldara Martin Alonso ◽  
Simon C Cork ◽  
Yue Ma ◽  
Myrtha Arnold ◽  
Herbert Herzog ◽  
...  
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Vagus Nerve ◽  
Low Dose ◽  
Peptide Yy ◽  
Sensory Nerve ◽  
Positive Control ◽  
Vagal Afferents ◽  
High Dose ◽  
Gut Hormone

Abstract Background: Drugs that safely promote weight loss are required to treat the obesity crisis. The gut hormone peptide YY 3-36 (PYY3-36) is secreted post-prandially to suppress appetite via the Y2 receptor (Y2R). However, it is unclear whether PYY3-36 acts directly on the Y2R in the hypothalamic arcuate nucleus (ARC) or the afferent vagus nerve to inhibit food intake. Understanding the pathways by which PYY3-36 mediates its anorectic effects may facilitate the therapeutic targeting of this system. Methods: Y2R knockdown in the ARC (ARC-Y2R-KD) was achieved by stereotactic injection of Cre-expressing adeno-associated virus (AAV-Cre) in Y2R-flox C57Bl/6 mice. Y2R KD in the vagus was achieved by bilateral microinjection of AAV-Cre into the nodose ganglia (NG), where the cell bodies of vagal afferents reside. An alternative germline model of sensory nerve Y2R knockdown was generated using Nav1.8-Cre mice crossed with the Y2R-flox strain (Nav1.8-Y2R-KD). Feeding behaviour over 10 days in metabolic cages and the effects of endogenously released (after oral gavage of a nutrient bolus) or exogenously-administered PYY3-36 were investigated. Results: NG-Y2R-KD animals had 60% reduction in NG Y2R mRNA but remained responsive to cholecystokinin, a positive control of vagal functionality. This is the first example of receptor specific adult vagal deafferentation in mice. The Nav1.8-Y2R-KD model achieved 30% receptor KD. Feeding patterns in the ARC-Y2R-KD and NG-Y2R-KD groups were highly different from their controls, with smaller, faster meals in the KD groups. The anorectic effects (at the next meal) of endogenous PYY3-36 were attenuated in NG-Y2R-KD. Low dose exogenous PYY3-36 at 5 µg/kg significantly reduced 2h post injection food intake (FI) in the control groups (n=8; P=0.045) but this was abrogated in the NG-Y2R-KD group. This pattern was mirrored in the Nav1.8-Y2R-KD model: low dose PYY3-36 significantly reduced FI 1h post-IP compared to vehicle in controls (-0.19±0.05 g; P =0.036; n=8) but not in the Nav1.8-Y2R-KD (-0.004±0.111 g; n=3). Peripherally-administered PYY3-36 at a high dose (30 µg/kg) decreased FI in all groups, including ARC-Y2R-KD. Summary: These results suggest that endogenous PYY3-36 modulates meal patterning. The vagus nerve mediates physiological PYY3-36 signalling but alternative pathways, not exclusively via the ARC, may be more important in mediating its pharmacological effects. This is relevant for the design of more effective weight loss agents.

scholarly journals Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

2016 ◽  
Vol 311 (6) ◽  
pp. E939-E948 ◽  
Author(s):  
Ruth B. S. Harris ◽  
Bhavna N. Desai
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Low Dose ◽  
High Dose ◽  
Rapid Weight Loss ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Arcuate Nuclei

Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis.

scholarly journals The Vagus Nerve Mediates the Physiological but not Pharmacological Effects of PYY3-36 on Food Intake

2020 ◽  
Author(s):  
A Martin Alonso ◽  
SC Cork ◽  
Y Ma ◽  
M Arnold ◽  
H Herzog ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Vagus Nerve ◽  
Peptide Yy ◽  
Therapeutic Potential ◽  
Pharmacological Effects ◽  
Gut Hormone ◽  
Reducing Activity ◽  
Higher Doses ◽  
Afferent Vagus

AbstractPeptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity mediated by the neuropeptide Y (NPY) Y2 receptor (Y2R). However, the neuronal pathways by which PYY3-36 acts to supress appetite are unclear. Determining how the PYY3-36 system physiologically regulates food intake may help exploit its therapeutic potential. Here we demonstrate that germline and post-natal targeted knockdown of the Y2R in the afferent vagus nerve inhibits the anorectic effects of physiologically-released PYY3-36, but not peripherally-administered higher doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is compensated for in the germline model. Loss of vagal Y2R signalling also alters meal patterning and accelerates gastric emptying. These results may facilitate the design of PYY-based anti-obesity agents.Abstract Figure

scholarly journals Peptide YY3–36 and Glucagon-Like Peptide-17–36 Inhibit Food Intake Additively

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5120-5127 ◽  
Author(s):  
Nicola M. Neary ◽  
Caroline J. Small ◽  
Maralyn R. Druce ◽  
Adrian J. Park ◽  
Sandra M. Ellis ◽  
...  
Keyword(s):  
Food Intake ◽  
Brain Stem ◽  
Low Dose ◽  
Arcuate Nucleus ◽  
Peptide Yy ◽  
High Dose ◽  
Hypothalamic Arcuate Nucleus ◽  
Inhibit Food Intake ◽  
Glucagon Like Peptide ◽  
The Brain

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY3–36 and GLP-17–36 inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY3–36 with GLP-17–36 in rodents and man. Whereas high-dose PYY3–36 (100 nmol/kg) and high-dose GLP-17–36 (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY3–36 (1 nmol/kg) and GLP-17–36 (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY3–36 or GLP-17–36 individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY3–36 and GLP-17–36 in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-17–36 (0.4 pmol/kg·min), PYY3–36 (0.4 pmol/kg·min), and PYY3–36 (0.4 pmol/kg·min) + GLP-17–36 (0.4 pmol/kg·min) on four separate days. Energy intake from a buffet meal after combined PYY3–36 + GLP-17–36 treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY3–36 and GLP-17–36, cosecreted after a meal, may inhibit food intake additively.

Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice

1997 ◽  
Vol 272 (2) ◽  
pp. R563-R569 ◽  
Author(s):  
L. R. Leon ◽  
W. Kozak ◽  
J. Peschon ◽  
M. J. Kluger
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Motor Activity ◽  
Knockout Mice ◽  
Low Dose ◽  
Late Phase ◽  
High Dose ◽  
Wild Type ◽  
Inflammatory Stimuli ◽  
Necrosis Factor

We examined the effects of injections of systemic [lipopolysaccharide (LPS), 2.5 mg/kg or 50 pg/kg ip] or local (turpentine, 100 microl sc) inflammatory stimuli on fever, motor activity, body weight, and food intake in tumor necrosis factor (TNF) double receptor (TNFR)-knockout mice. A high dose of LPS resulted in exacerbated fevers in TNFR-knockout mice compared with wild-type mice for the early phase of fever (3-15 h); the late phase of fever (16-24 h) and fevers to a low dose of LPS were similar in both groups. Motor activity, body weight, and food intake were similarly reduced in both groups of mice after LPS administration. In response to turpentine, TNFR-knockout and wild-type mice developed virtually identical responses to all variables monitored. These results suggest that 1) TNF modulates fevers to LPS dose dependently, 2) TNF does not modulate fevers to a subcutaneous injection of turpentine, and 3) knockout mice may develop cytokine redundancy in the regulation of the acute phase response to intraperitoneally injected LPS or subcutaneously injected turpentine.

Diuretic activities of fayiren and coix seed in normal rats

2020 ◽  
Author(s):  
Tao Hong ◽  
Hao Chen ◽  
Li Liu ◽  
Weiqi Liu ◽  
Longxue Li ◽  
...  
Keyword(s):  
Low Dose ◽  
Urine Volume ◽  
Positive Control ◽  
Total Output ◽  
High Dose ◽  
Model Group ◽  
Urine Ph ◽  
Coix Seed ◽  
The Difference ◽  
Time Point

Abstract Background Coix seed is a traditional Chinese medicine with pharmacological effects and food efficacy. It is well-know and widely used in China and other Asian countries. Fayiren is a new artillery material processed from Coix Seed. This is the first study of the diuretic activities of Fayiren and coix seed in normal rats. Methods Forty-eight rats were randomly divided into 6 groups (8 rats/group) according to body mass and urine volume stratification, namely model (physiological saline) group, positive control (furosemide 20 mg/kg) group, coix seed (1666 mg/kg) group, low-dose of Fayiren group (166 mg/kg) and high-dose Fayiren group (1666 mg/kg). Rats were fasted for 16 h before the experiment, with normal water supply. Immediately after administration, each group of rat was placed in a metabolic cage, and urine was collected once after every hour for a total of 6 times. The urine volume at each time point for collection was measured, and then totaled. After the 6 h recording procedure, the treatments were administered once a day and the urine was collected at the 24th, 48th, 72th, 96th, 110th, 134th, and 158th hours from the start respectively. The urine pH and Na +, K +, Ca 2+, Cl - concentrations at each time point of each group of rats were measured. The contents of ALD, ANP, ADH, Na+-K+-ATPase, the gene expression and protein levels of AQP1, AQP2 and AQP3 in urine of rats in each group were determined. SPSS22.0 statistical software was used to analyze the experimental data. One way ANOVA and multiple comparisons between LSD groups were performed. The difference is considered significant When p < 0.05 or p < 0.01. Results After the administration of Fayiren and coix seed, compared with normal rats, the total output of urine in the high-dose coix seed & Fayiren group and the positive control group both increased; In addition, the contents of Na+ and Cl-in urine in these groups increased as well. However, the content of K+ did not increase in all groups. Contents of ALD and ADH was decreased and increased contents of ANP observed in urine in both high-dose and low-dose Fayiren groups with significant differences from model group (P < 0.05). Coix seed significantly reduced ADH and increased ANP levels compared with model group (P < 0.05). There was no obvious change in the urine pH content in urine of all rats. All the aquaporin (AQP1, AQP2, and AQP3) contents were decreased comparing to the model group, the coix seed group, as well as the Fayiren group. The effect of coix seed was particularly notable on AQP2, and the difference was significant against the Furosemide group (P < 0.05). By contrast, Fayiren showed greater effects on AQP1 and AQP3, with statistically significant difference comparing to the model group (P༜0.05). Conclusions This study will provide experimental evidence for explaining the different mechanisms of diuretic effects in natural medicine use of coix seed and artillery material processed from Coix Seed. The Fayiren may affect the reabsorption of water in the kidney through mechanisms related to increased ANP secretion,decreased ALD and ADH secretion in urine, and it significantly affect the expression of aquaporin 1 and aquaporin 3. However, coix seed may increase ANP but decreased ADH secretion, further affecting the expression of aquaporin2 and exert diuretic effect.

scholarly journals A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy

2020 ◽  
Vol 106 (1) ◽  
pp. e204-e216
Author(s):  
Conor F Murphy ◽  
Nicholas Stratford ◽  
Neil G Docherty ◽  
Brendan Moran ◽  
Jessie A Elliott ◽  
...  
Keyword(s):  
Weight Loss ◽  
Pilot Study ◽  
Food Intake ◽  
Eating Behavior ◽  
Hormone Secretion ◽  
Symptom Burden ◽  
Octreotide Lar ◽  
Gut Hormone ◽  
Ad Libitum ◽  
Brain Reward

Abstract Background Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated postprandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among postesophagectomy patients with unintentional weight loss. Methods This pilot study prospectively studied postoperative patients with 10% or greater body weight loss (BWL) beyond 1 year who were candidates for clinical treatment with long-acting octreotide (LAR). Before and after 4 weeks of treatment, gut hormone secretion, food cue reactivity (functional magnetic resonance imaging), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. Results Eight patients (7 male, age: mean ± SD 62.8 ± 9.4 years, postoperative BWL: 15.5 ± 5.8%) participated. Octreotide LAR did not significantly suppress total postprandial plasma glucagon-like peptide-1 response at 4 weeks (P = .08). Postprandial symptom burden improved after treatment (Sigstad score median [range]: 12 [2-28] vs 8 [3-18], P = .04) but weight remained stable (pre: 68.6 ± 12.8 kg vs post: 69.2 ± 13.4 kg, P = .13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P = .41) nor ad libitum food intake(P = .46). Conclusion The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses 4 weeks after octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter interdose interval may be required to optimize the intervention.

scholarly journals How Satiating Are the ‘Satiety’ Peptides: A Problem of Pharmacology versus Physiology in the Development of Novel Foods for Regulation of Food Intake

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1517 ◽  
Author(s):  
Jia Jiet Lim ◽  
Sally D. Poppitt
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Energy Intake ◽  
Peptide Yy ◽  
Behavioural Change ◽  
Eating Behaviour ◽  
Predictive Biomarkers ◽  
Negative Energy ◽  
Novel Foods ◽  
Glucagon Like Peptide 1

Developing novel foods to suppress energy intake and promote negative energy balance and weight loss has been a long-term but commonly unsuccessful challenge. Targeting regulation of appetite is of interest to public health researchers and industry in the quest to develop ‘functional’ foods, but poor understanding of the underpinning mechanisms regulating food intake has hampered progress. The gastrointestinal (GI) or ‘satiety’ peptides including cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) secreted following a meal, have long been purported as predictive biomarkers of appetite response, including food intake. Whilst peptide infusion drives a clear change in hunger/fullness and eating behaviour, inducing GI-peptide secretion through diet may not, possibly due to modest effects of single meals on peptide levels. We conducted a review of 70 dietary preload (DIET) and peptide infusion (INFUSION) studies in lean healthy adults that reported outcomes of CCK, GLP-1 and PYY. DIET studies were acute preload interventions. INFUSION studies showed that minimum increase required to suppress ad libitum energy intake for CCK, GLP-1 and PYY was 3.6-, 4.0- and 3.1-fold, respectively, achieved through DIET in only 29%, 0% and 8% of interventions. Whether circulating ‘thresholds’ of peptide concentration likely required for behavioural change can be achieved through diet is questionable. As yet, no individual or group of peptides can be measured in blood to reliably predict feelings of hunger and food intake. Developing foods that successfully target enhanced secretion of GI-origin ‘satiety’ peptides for weight loss remains a significant challenge.

scholarly journals Combination Therapy with Amylin and Peptide YY[3–36] in Obese Rodents: Anorexigenic Synergy and Weight Loss Additivity

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6054-6061 ◽  
Author(s):  
Jonathan D. Roth ◽  
Todd Coffey ◽  
Carolyn M. Jodka ◽  
Holly Maier ◽  
Jennifer R. Athanacio ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Peptide Yy ◽  
Peptide Hormone ◽  
Short Term ◽  
Subcutaneous Infusion ◽  
Body Weight Reduction ◽  
Diet Induced Obesity ◽  
Circulating Levels

Circulating levels of the pancreatic β-cell peptide hormone amylin and the gut peptide PYY[3–36] increase after nutrient ingestion. Both have been implicated as short-term signals of meal termination with anorexigenic and weight-reducing effects. However, their combined effects are unknown. We report that the combination of amylin and PYY[3–36] elicited greater anorexigenic and weight-reducing effects than either peptide alone. In high-fat-fed rats, a single ip injection of amylin (10 μg/kg) plus PYY[3–36] (1000 μg/kg) reduced food intake for 24 h (P &lt; 0.05 vs. vehicle), whereas the anorexigenic effects of either PYY[3–36] or amylin alone began to diminish 6 h after injection. These anorexigenic effects were dissociable from changes in locomotor activity. Subcutaneous infusion of amylin plus PYY[3–36] for 14 d suppressed food intake and body weight to a greater extent than either agent alone in both rat and mouse diet-induced obesity (DIO) models (P &lt; 0.05). In DIO-prone rats, 24-h metabolic rate was maintained despite weight loss, and amylin plus PYY[3–36] (but not monotherapy) increased 24-h fat oxidation (P &lt; 0.05 vs. vehicle). Finally, a 4 × 3 factorial design was used to formally describe the interaction between amylin and PYY[3–36]. DIO-prone rats were treated with amylin (0, 4, 20, and 100 μg/kg·d) and PYY[3–36] (0, 200, 400 μg/kg·d) alone and in combination for 14 d. Statistical analyses revealed that food intake suppression with amylin plus PYY[3–36] treatment was synergistic, whereas body weight reduction was additive. Collectively, these observations highlight the importance of studying peptide hormones in combination and suggest that integrated neurohormonal approaches may hold promise as treatments for obesity.

scholarly journals Daily, intermittent intravenous infusion of peptide YY(3-36) reduces daily food intake and adiposity in rats

2006 ◽  
Vol 290 (2) ◽  
pp. R298-R305 ◽  
Author(s):  
Prasanth K. Chelikani ◽  
Alvin C. Haver ◽  
Joseph R. Reeve ◽  
David A. Keire ◽  
Roger D. Reidelberger
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Intravenous Infusion ◽  
Peptide Yy ◽  
Subcutaneous Administration ◽  
Chronic Administration ◽  
Daily Food Intake ◽  
Daily Food ◽  
Sustained Reduction ◽  
Gut Hormone

The gut hormone peptide YY(3-36) [PYY(3-36)] decreases food intake when administered by intravenous infusion to lean and obese humans and rats. Whether chronic administration of PYY(3-36) produces a sustained reduction in food intake and adiposity is the subject of intense debate. Batterham et al. (R. L. Batterham, M. A. Cowley, C. J. Small, H. Herzog, M. A. Cohen, C. L. Dakin, A. M. Wren, A. E. Brynes, M. J. Low, M. A. Ghatei, R. D. Cone, and S. R. Bloom. Nature 418: 650–654, 2002) first reported that PYY(3-36) reduces food intake and weight gain in rats when injected into the peritoneal cavity twice daily for 7 days. Numerous laboratories have failed to confirm that daily injections of PYY(3-36) decrease body weight. Continuous subcutaneous administration of PYY(3-36) by osmotic minipump has been reported to reduce daily food intake in rodents but only during the first 3–4 days of administration. Here we show the effects of different daily patterns of intravenous infusion of PYY(3-36) on food intake, body weight, and adiposity in rats tethered via infusion swivels to computer-controlled pumps. Measurement of food bowl weight recorded by computer every 20 s permitted daily assessment of the instantaneous effects of PYY(3-36) administration on food intake and meal patterns. One-hour intravenous infusions of PYY(3-36) at 30 pmol·kg−1·min−1 every other hour for 10 days produced a sustained reduction in daily food intake of ∼20% and decreased body weight and adiposity by 7 and 35%, respectively. Thus dosage pattern is critical for producing a sustained effect of PYY(3-36) on food intake and adiposity.

scholarly journals Evaluation of anti-ulcer activity of 4-hydrooxy benzalydehide against NSAIDs induced ulcers in rats

2021 ◽  
Vol 9 (5) ◽  
pp. 1412
Author(s):  
Rupali V. Jadhav ◽  
V. K. Redasani ◽  
Shankar B. Kalbhare ◽  
Karishma Yadav ◽  
Aryan Langeh ◽  
...  
Keyword(s):  
Low Dose ◽  
Positive Control ◽  
Gastric Volume ◽  
Control Group ◽  
High Dose ◽  
Antiulcer Activity ◽  
Ulcer Index ◽  
Pylorus Ligation ◽  
The Impact ◽  
Intermediate Dose

Background: The aim of this study was to evaluate antiulcer activity of 4-hydroxybenzaldehyde against NSAIDs induced ulcer in rats based differences in its morphology, distance with other external landmarks and also to sigmoid and transverse sinuses.Methods: The antiulcer activity of 4-HBD was evaluated using pylorus ligation-aspirin induced ulcer method. Animals of this models were treated with 4-HBD (50mg/kg, 100mg/kg and 150mg/kg).Results: It has been observed that 4-HBD at low dose (50mg/kg), intermediate dose (100mg/kg) and high dose (150mg/kg) showed significant increase in pH, significant decrease in gastric volume, significant decrease in ulcer index and significant decrease in total acidity.Conclusions: The impact of 4-HBD therapy with intermediate (100mg/kg, p.o.) dose was observed to be similar with the positive control group.  

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