scholarly journals The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Amy A Worth ◽  
Rosemary Shoop ◽  
Katie Tye ◽  
Claire H Feetham ◽  
Giuseppe D'Agostino ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Food Intake ◽  
Weight Reduction ◽  
Area Postrema ◽  
Metabolic Effects ◽  
Therapeutic Drug ◽  
Neutralising Antibodies ◽  
Neuronal Signalling ◽  
Pre Treatment

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

Secretin as a satiation whisperer with the potential to turn into an obesity-curbing knight

Endocrinology ◽  
2021 ◽  
Author(s):  
Katharina Schnabl ◽  
Yongguo Li ◽  
Mueez U-Din ◽  
Martin Klingenspor
Keyword(s):  
Bariatric Surgery ◽  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Weight Control ◽  
Therapeutic Potential ◽  
Physiological Mechanism ◽  
Gut Hormones ◽  
Metabolic Effects ◽  
Beneficial Effects

Abstract The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, it only recently has been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these two entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery as well as chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin’s metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

Bimatoprost promotes satiety and attenuates body weight in rats fed standard or obesity-promoting diets.

2020 ◽  
Author(s):  
Clayton Spada ◽  
Chau Vu ◽  
Iona Raymond ◽  
Warren Tong ◽  
Chia-Lin Chuang ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Gastric Emptying ◽  
Food Intake ◽  
Visceral Fat ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Sprague Dawley ◽  
Hormone Levels ◽  
Gut Hormone

Abstract Background Bimatoprost negatively regulates adipogenesis in vitro and likely participates in a negative feedback loop on anandamide-induced adipogenesis. Here, we investigate the broader metabolic effects of bimatoprost action in vivo in rats under both normal state and obesity-inducing conditions. Methods Male Sprague Dawley rats were a fed standard chow (SC) diet in conjunction with dermally applied bimatoprost treatment for a period of 9–10 weeks. Body weight gain, energy expenditure, food intake, and hormones associated with satiety were measured. Gastric emptying was also separately evaluated. In obesity-promoting diet studies, rats were fed a cafeteria diet (CAF) and gross weight, fat accumulation in SQ, visceral fat and liver was evaluated together with standard serum chemistry. Results Chronic bimatoprost administration attenuated weight gain in rats fed either standard or obesity-promoting diets over a 9–10 weeks. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Additionally, SQ and visceral fat mass was distinctly affected by treatment. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Conclusions These findings suggest that bimatoprost (and possibly prostamide F2α) regulates energy homeostasis through actions on dietary intake. These actions likely counteract the metabolic actions of anandamide through the endocannabinoid system potentially revealing a new pathway that could be exploited for therapeutic development.

scholarly journals Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 88 ◽  
Author(s):  
Mehdi Labyb ◽  
Chloé Chrétien ◽  
Aurélie Caillon ◽  
Françoise Rohner-Jeanrenaud ◽  
Jordi Altirriba
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Leptin Resistance ◽  
Obese Mice ◽  
Short Term ◽  
Continuous Administration ◽  
Pre Treatment ◽  
Treatment Of Obesity

Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.

scholarly journals Antiobesity Effects of the β-Cell Hormone Amylin in Diet-Induced Obese Rats: Effects on Food Intake, Body Weight, Composition, Energy Expenditure, and Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5855-5864 ◽  
Author(s):  
Jonathan D. Roth ◽  
Heather Hughes ◽  
Eric Kendall ◽  
Alain D. Baron ◽  
Christen M. Anderson
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Respiratory Quotient ◽  
Metabolic Effects ◽  
Mrna Levels ◽  
Lean Tissue ◽  
Reduced Body ◽  
Diet Induced Obesity ◽  
Cell Hormone

Effects of amylin and pair feeding (PF) on body weight and metabolic parameters were characterized in diet-induced obesity-prone rats. Peripherally administered rat amylin (300 μg/kg·d, 22d) reduced food intake and slowed weight gain: approximately 10% (P < 0.05), similar to PF. Fat loss was 3-fold greater in amylin-treated rats vs. PF (P < 0.05). Whereas PF decreased lean tissue (P < 0.05 vs. vehicle controls; VEH), amylin did not. During wk 1, amylin and PF reduced 24-h respiratory quotient (mean ± se, 0.82 ± 0.0, 0.81 ± 0.0, respectively; P < 0.05) similar to VEH (0.84 ± 0.01). Energy expenditure (EE mean ± se) tended to be reduced by PF (5.67 ± 0.1 kcal/h·kg) and maintained by amylin (5.86 ± 0.1 kcal/h·kg) relative to VEH (5.77 ± 0.0 kcal/h·kg). By wk 3, respiratory quotient no longer differed; however, EE increased with amylin treatment (5.74 ± 0.09 kcal/·kg; P < 0.05) relative to VEH (5.49 ± 0.06) and PF (5.38 ± 0.07 kcal/h·kg). Differences in EE, attributed to differences in lean mass, argued against specific amylin-induced thermogenesis. Weight loss in amylin and pair-fed rats was accompanied by similar increases arcuate neuropeptide Y mRNA (P < 0.05). Amylin treatment, but not PF, increased proopiomelanocortin mRNA levels (P < 0.05 vs. VEH). In a rodent model of obesity, amylin reduced body weight and body fat, with relative preservation of lean tissue, through anorexigenic and specific metabolic effects.

Mo1181 An Outpatient 1-Year Weight Reduction Program for Obese Patients - Effects on Body Weight and Hormones Regulating Food Intake

2012 ◽  
Vol 142 (5) ◽  
pp. S-614-S-615
Author(s):  
Andreas Stengel ◽  
Andrea Riedl ◽  
Anne Ahnis ◽  
Andrea Figura ◽  
Tobias Hofmann ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Weight Reduction ◽  
Obese Patients ◽  
Weight Reduction Program ◽  
Reduction Program

scholarly journals Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

2008 ◽  
Vol 295 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Sabine Strassburg ◽  
Stefan D. Anker ◽  
Tamara R. Castaneda ◽  
Lukas Burget ◽  
Diego Perez-Tilve ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Positive Energy ◽  
High Dose ◽  
Growth Hormone Secretagogue

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg−1·day−1 using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

scholarly journals GFRAL-expressing neurons suppress food intake via aversive pathways

2021 ◽  
Vol 118 (8) ◽  
pp. e2021357118
Author(s):  
Paul V. Sabatini ◽  
Henriette Frikke-Schmidt ◽  
Joe Arthurs ◽  
Desiree Gordian ◽  
Anita Patel ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Area Postrema ◽  
Mechanisms Of Action ◽  
Parabrachial Nucleus ◽  
Potential Treatment ◽  
Exciting Opportunity ◽  
Wide Range ◽  
Restricted Expression Pattern ◽  
Meal Ingestion

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non–meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

scholarly journals GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats

2020 ◽  
Vol 12 (533) ◽  
pp. eaay8071 ◽  
Author(s):  
Samantha M. Fortin ◽  
Rachele K. Lipsky ◽  
Rinzin Lhamo ◽  
Jack Chen ◽  
Eun Kim ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Male Rats ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity ◽  
Cellular Phenotypes ◽  
Sites Of Action

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is approved for the treatment of obesity; however, there is still much to be learned regarding the neuronal sites of action that underlie its suppressive effects on food intake and body weight. Peripherally administered liraglutide in rats acts in part through central GLP-1Rs in both the hypothalamus and the hindbrain. Here, we extend findings supporting a role for hindbrain GLP-1Rs in mediating the anorectic effects of liraglutide in male rats. To dissociate the contribution of GLP-1Rs in the area postrema (AP) and the nucleus tractus solitarius (NTS), we examined the effects of liraglutide in both NTS AAV-shRNA–driven Glp1r knockdown and AP-lesioned animals. Knockdown of NTS GLP-1Rs, but not surgical lesioning of the AP, attenuated the anorectic and body weight–reducing effects of acutely delivered liraglutide. In addition, NTS c-Fos responses were maintained in AP-lesioned animals. Moreover, NTS Glp1r knockdown was sufficient to attenuate the intake- and body weight–reducing effects of chronic daily administered liraglutide over 3 weeks. Development of improved obesity pharmacotherapies requires an understanding of the cellular phenotypes targeted by GLP-1R agonists. Fluorescence in situ hybridization identified Glp1r transcripts in NTS GABAergic neurons, which when inhibited using chemogenetics, attenuated the food intake– and body weight–reducing effects of liraglutide. This work demonstrates the contribution of NTS GLP-1Rs to the anorectic potential of liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling.

Level of satiety: in vitro energy metabolism in brain during hypophagic and hyperphagic body weight recovery

1989 ◽  
Vol 257 (6) ◽  
pp. R1322-R1327 ◽  
Author(s):  
T. R. Kasser ◽  
R. B. Harris ◽  
R. J. Martin
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Fatty Acid ◽  
Food Intake ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Area Postrema ◽  
Tube Feeding ◽  
Acid Oxidation

Rates of in vitro glucose and fatty acid oxidation were examined in four brain sites during hypophagic and hyperphagic recovery of normal body weight. Rats were fed 40, 100, or 160% of normal intake, via gastric intubation, for 3 wk. Another group of rats was starved until body weight loss was equivalent to weight loss in 40%-fed rats. Groups of rats were killed at the conclusion of tube feeding or fasting and at specific periods during recovery of body weight. Brain sites examined were the ventrolateral hypothalamus (VLH), ventromedial hypothalamus (VMH), a caudal brain stem site encompassing the area postrema-nucleus of the solitary tract (AP-NTS), and cortex. During recovery, rats previously fed 160% of normal intake (anorectic) maintained low rates of VLH fatty acid oxidation and were hypophagic until most excess fat was depleted. Conversely, rats previously fed 40% of normal intake (hungry) maintained high rates of VLH fatty acid oxidation and were hyperphagic until most deficient fat was repleted. Rats previously starved maintained high rates of VLH fatty acid oxidation during hyperphagic recovery, although levels of VLH fatty acid oxidation and food intake were initially low on refeeding. Rates of glucose oxidation in the brain sites examined did not relate well to energy balance status and the needed adjustments in food intake. The results indicated that the level of glucose oxidation in the VLH and AP-NTS responded to the level of energy immediately coming into the system (food intake).(ABSTRACT TRUNCATED AT 250 WORDS)

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