scholarly journals GLP-1 and weight loss: unraveling the diverse neural circuitry

2016 ◽  
Vol 310 (10) ◽  
pp. R885-R895 ◽  
Author(s):  
Scott E. Kanoski ◽  
Matthew R. Hayes ◽  
Karolina P. Skibicka
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Direct Action ◽  
Neural Systems ◽  
Reduce Food Intake ◽  
Hypothalamic Area ◽  
Medial Nucleus ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1 analogs potently reduce food intake and body weight, and recent discoveries reveal that peripheral administration of these drugs reduces food intake largely through humoral pathways involving direct action on brain GLP-1 receptors (GLP-1R). Thus, it is of critical importance to understand the neural systems through which GLP-1 and long-acting GLP-1 analogs reduce food intake and body weight. In this review, we discuss several neural, physiological, cellular and molecular, as well as behavioral mechanisms through which peripheral and central GLP-1R signaling reduces feeding. Particular attention is devoted to discussion regarding the numerous neural substrates through which GLP-1 and GLP-1 analogs act to reduce food intake and body weight, including various hypothalamic nuclei (arcuate nucleus of the hypothalamus, periventricular hypothalamus, lateral hypothalamic area), hindbrain nuclei (parabrachial nucleus, medial nucleus tractus solitarius), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry [ventral tegmental area (VTA) and nucleus accumbens (NAc)]. In some of these nuclei [VTA, NAc, and vHP], GLP-1R activation reduces food intake and body weight without concomitant nausea responses, suggesting that targeting these specific pathways may be of particular interest for future obesity pharmacotherapy. The widely distributed neural systems through which GLP-1 and GLP-1 analogs act to reduce body weight highlight the complexity of the neural systems regulating energy balance, as well as the challenges for developing effective obesity pharmacotherapies that reduce feeding without producing parallel negative side effects.

scholarly journals Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

2014 ◽  
Vol 307 (4) ◽  
pp. R465-R470 ◽  
Author(s):  
Amber L. Alhadeff ◽  
Harvey J. Grill
Keyword(s):  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Progressive Ratio ◽  
Ratio Schedule ◽  
Inhibitory Effects ◽  
Medial Nucleus ◽  
Neural Processes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Central glucagon-like peptide-1 receptor (GLP-1R) signaling reduces food intake by affecting a variety of neural processes, including those mediating satiation, motivation, and reward. While the literature suggests that separable neurons and circuits control these processes, this notion has not been adequately investigated. The intake inhibitory effects of GLP-1R signaling in the hindbrain medial nucleus tractus solitarius (mNTS) have been attributed to interactions with vagally transmitted gastrointestinal satiation signals that are also processed by these neurons. Here, behavioral and pharmacological techniques are used to test the novel hypothesis that the reduction of food intake following mNTS GLP-1R stimulation also results from effects on food-motivated appetitive behaviors. Results show that mNTS GLP-1R activation by microinjection of exendin-4, a long-acting GLP-1R agonist, reduced 1) intake of a palatable high-fat diet, 2) operant responding for sucrose under a progressive ratio schedule of reinforcement and 3) the expression of a conditioned place preference for a palatable food. Together, these data demonstrate that the intake inhibitory effects of mNTS GLP-1R signaling extend beyond satiation and include effects on food reward and motivation that are typically ascribed to midbrain and forebrain neurons.

scholarly journals Repeated Intracerebroventricular Administration of Glucagon-Like Peptide-1-(7–36) Amide or Exendin-(9–39) Alters Body Weight in the Rat**This work was supported by the United Kingdom Medical Research Council.

Endocrinology ◽  
1999 ◽  
Vol 140 (1) ◽  
pp. 244-250 ◽  
Author(s):  
Karim Meeran ◽  
Donal O’Shea ◽  
C. Mark B. Edwards ◽  
Mandy D. Turton ◽  
Melanie M. Heath ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Research Council ◽  
Medical Research Council ◽  
Reduce Food Intake ◽  
The United Kingdom ◽  
Ad Libitum ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Central nervous system glucagon-like peptide-1-(7–36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (icv) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9–39), affects food intake and body weight. Daily icv injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 ± 5 g (P < 0.02 compared with saline-injected controls). Daily icv administration of 30 nmol exendin-(9–39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 ± 2 g (P < 0.02 compared with saline-injected controls). Twice daily icv injections of 30 nmol exendin-(9–39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 ± 4 g compared with 14 ± 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to icv GLP-1 or exendin-(9–39). GLP-1 may thus be involved in the regulation of body weight in the rat.

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.

scholarly journals Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3473-3483 ◽  
Author(s):  
Yan Yang ◽  
Alexander A. Moghadam ◽  
Zachary A. Cordner ◽  
Nu-Chu Liang ◽  
Timothy H. Moran
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Food Intake ◽  
Repeated Administration ◽  
Reduce Food Intake ◽  
Related Protein ◽  
Sprague Dawley ◽  
Long Acting ◽  
Rebound Increase ◽  
Agouti Gene

Abstract Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, ip, twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.

scholarly journals GLP-1 Neurons in the Nucleus of the Solitary Tract Project Directly to the Ventral Tegmental Area and Nucleus Accumbens to Control for Food Intake

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 647-658 ◽  
Author(s):  
Amber L. Alhadeff ◽  
Laura E. Rupprecht ◽  
Matthew R. Hayes
Keyword(s):  
Body Weight ◽  
Nucleus Accumbens ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
Current Data ◽  
Solitary Tract ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Central glucagon-like-peptide-1 (GLP-1) receptor activation reduces food intake; however, brain nuclei and mechanism(s) mediating this effect remain poorly understood. Although central nervous system GLP-1 is produced almost exclusively in the nucleus of the solitary tract in the hindbrain, GLP-1 receptors (GLP-1R) are expressed throughout the brain, including nuclei in the mesolimbic reward system (MRS), e.g. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Here, we examine the MRS as a potential site of action for GLP-1-mediated control of food intake and body weight. Double immunohistochemistry for Fluorogold (monosynaptic retrograde tracer) and GLP-1 neuron immunoreactivity indicated that GLP-1-producing nucleus tractus solitarius neurons project directly to the VTA, the NAc core, and the NAc shell. Pharmacological data showed that GLP-1R activation in the VTA, NAc core, and NAc shell decreased food intake, especially of highly-palatable foods, and body weight. Moreover, blockade of endogenous GLP-1R signaling in the VTA and NAc core resulted in a significant increase in food intake, establishing a physiological relevance for GLP-1 signaling in the MRS. Current data highlight these nuclei within the MRS as novel sites for GLP-1R-mediated control of food intake and body weight.

scholarly journals Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3103-3112 ◽  
Author(s):  
Scott E. Kanoski ◽  
Samantha M. Fortin ◽  
Myrtha Arnold ◽  
Harvey J. Grill ◽  
Matthew R. Hayes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Food Intake ◽  
Vagal Afferents ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting ◽  
Higher Doses ◽  
Cns Delivery

The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after ip delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3rd ICV)] of the GLP-1R antagonist exendin-(9–39) (100 μg), attenuated the intake suppression by ip liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9–39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after ip delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. Conclusion: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size

2007 ◽  
Vol 293 (3) ◽  
pp. R983-R987 ◽  
Author(s):  
Karen A. Scott ◽  
Timothy H. Moran
Keyword(s):  
Food Intake ◽  
Rhesus Macaques ◽  
Specific Effect ◽  
Meal Size ◽  
Reduce Food Intake ◽  
Dependent Manner ◽  
Primate Model ◽  
Glucagon Like Peptide 1 ◽  
Long Acting ◽  
Dose Dependent

Exendin-4 (Ex4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to reduce food intake and suppress gastric emptying in rodents and humans. In this study we investigated the effects of peripheral administration of Ex4 on food intake and meal patterns in adult male rhesus macaques. Rhesus macaques ( n = 4) that had been trained to lever press for food pellets were injected intramuscularly 15 min before the start of their 6-h daily feeding period. Ex4 was given at doses of 0.10, 0.32, 0.56, 1.0, and 3.0 μg/kg. Ex4 suppressed food intake in a dose-dependent manner, with the 3.0 μg/kg dose completely preventing feeding during the 6-h period and the 0.10 μg/kg dose suppressing intake by 17%. Doses of 0.32, 0.56, 1.0, and 3.0 μg/kg caused significant reductions in cumulative intake at all six hourly time points. Ex4 inhibited food intake through a specific effect on meal size. Meal size was significantly reduced in a dose-dependent manner with significant reductions at the 0.32 and 1.0 μg/kg doses ( P < 0.05). Day 2 and 3intakes returned to baseline levels with no compensation for Ex4-induced feeding suppression. Administration of doses of 0.32 and 0.56 μg/kg Ex4 over 5 consecutive days led to sustained reductions in intake with no evidence of compensation. Again, these reductions were due to specific effects on meal size. These results demonstrate that activation of GLP-1 pathways has potent effects on the controls of meal size and overall food intake in a nonhuman primate model.

scholarly journals GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist Induced Nausea and Emesis in Preclinical Models

2021 ◽  
Author(s):  
Tito Borner ◽  
Caroline E. Geisler ◽  
Samantha M. Fortin ◽  
Richard Cosgrove ◽  
Jorge Alsina-Fernandez ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Body Weight Loss ◽  
Diabetes Patient ◽  
Obesity And Diabetes ◽  
Nausea And Emesis ◽  
Glucagon Like Peptide 1 ◽  
Cellular Phenotypes

Glucagon-like peptide-1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by side effects including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Utilizing single-nuclei RNA-sequencing, we identified the cellular phenotypes of AP/NTS GIPR- and GLP-1R-expressing cells on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in GABAergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

scholarly journals Preclinical Weight Loss Efficacy of AM833 in Combination With Semaglutide in Rodent Models of Obesity

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A54-A54
Author(s):  
Linu M John ◽  
Thomas Kruse ◽  
Kirsten Raun
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Weight Management ◽  
Pancreatic Beta Cells ◽  
High Energy ◽  
Clinical Development ◽  
Reduce Food Intake ◽  
Rodent Models ◽  
Long Acting

Abstract Weight management pharmacotherapies seldom induce body weight loss that is comparable to that produced by bariatric surgery. In this regard, combination therapies targeting multiple signaling pathways that regulate energy balance may provide a means to achieve greater weight loss efficacy while also allowing the use of lower doses of each drug, and thus mitigating potential gastrointestinal tolerability issues commonly observed with current therapeutics for weight management. Amylin and GLP-1 are peptide hormones that regulate appetite. Upon ingestion of a meal, amylin is co-secreted with insulin from pancreatic beta-cells, while GLP-1 is secreted from enteroendocrine cells in the intestine. Both native peptides have a short half-life and reduce food intake, delay gastric emptying and decrease glucagon levels. Amylin and GLP-1 analogues have been developed for the treatment of diabetes, as well as weight management. The long-acting once-weekly GLP-1 analogue, semaglutide is approved for the treatment of type 2 diabetes and is in clinical development for weight management. AM833 (NNC0174-0833) is a long-acting, once-weekly human amylin analogue that is also in clinical development for weight management. Here, we present the combined effect of AM833 and semaglutide on weight loss in rodent models of obesity. Diet-induced obese (DIO) rats and mice on a high energy diet were dosed subcutaneously once-daily for 24 or 28 days with sub-maximal doses of AM833, semaglutide or two modes of combination treatments. The first combination mode consisted of concurrent co-dosing of both drugs, while the second entailed add-on of AM833 after one week of treatment with semaglutide. Body weight and food intake were measured daily. Body composition was assessed by magnetic resonance scan pre- and post-treatment. In the DIO rat, both concurrent (-13.1% ± 0.7%) and add-on (-12.8% ± 1.2%) treatment modes induced equivalent weight loss that was greater than each monotherapy (-6.3% ± 0.7%, 2 nmol/kg semaglutide and -5.8% ± 0.9%, 2 nmol/kg AM833) relative to initial body weights. Both combination groups achieved normalization of body weight to that of lean age-matched control rats. Reductions in cumulative food intake corresponded with the extent of weight loss. In the DIO mouse, weight loss in the combination groups was not significantly different (-9.6% ± 1.5%, concurrent vs. -11.5% ± 1.2%, add-on) but was greater than that observed in each monotherapy group (-1.9% ±1.2%, 1 nmol/kg semaglutide and +1.5% ± 2.2%, 10 nmol/kg AM833). In the DIO mouse, body weight did not normalize to match that of lean controls with combination treatment. In both rodent models, combination therapy at submaximal doses of AM833 and semaglutide achieved significantly greater weight loss compared to the monotherapy groups highlighting the potential of this combination for further clinical development.

Peptide signals regulating food intake and energy homeostasis

2002 ◽  
Vol 80 (5) ◽  
pp. 396-406 ◽  
Author(s):  
James E Blevins ◽  
Michael W Schwartz ◽  
Denis G Baskin
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Paraventricular Nucleus ◽  
Energy Homeostasis ◽  
Nucleus Tractus Solitarius ◽  
Nerve Fibers ◽  
Ingestive Behavior ◽  
Meal Size ◽  
Medial Nucleus ◽  
Fos Expression

The adiposity hormone leptin has been shown to decrease food intake and body weight by acting on neuropeptide circuits in the hypothalamus. However, it is not clear how this primary hypothalamic action of leptin is translated into a change in food intake. We hypothesize that the behavioral effect of leptin ultimately involves the integration of neuronal responses in the forebrain with those in the nucleus tractus solitarius in the caudal brainstem, where ingestive behavior signals are received from the gastrointestinal system and the blood. One example is the peptide cholecystokinin, which is released from the gut following ingestion of a meal and acts via vagal afferent nerve fibers to activate medial nucleus tractus solitarius neurons and thereby decrease meal size. While it is established that leptin acts in the arcuate nucleus in the hypothalamus to stimulate anorexigenic neurons that inhibit food intake while simulataneously inhibiting orexigenic neurons that increase food intake, the mechanisms linking these effects with regions of the caudal brainstem that integrate cues related to meal termination are unclear. Based on an increasing body of supportive data, we hypothesize that this integration involves a pathway comprising descending projections from neurons from the paraventricular nucleus to neurons within the nucleus tractus solitarius that are activated by meal-related satiety factors. Leptin's anorexic effect comprises primarily decreased meal size, and at subthreshold doses for eliciting an effect on food intake, leptin intensifies the satiety response to circulating cholecystokinin. The location of neurons subserving the effects of intracerebroventricular administration of leptin and intraperitoneal injection of cholecystokinin on food intake has been identified by analysis of Fos expression. These studies reveal a distribution that includes the paraventricular nucleus and regions within the caudal brainstem, with the medial nucleus tractus solitarius having the most pronounced Fos expression in response to leptin and cholecystokinin, and support the hypothesis that the long-term adiposity signal leptin and the short-term satiety signal cholecystokinin act in concert to maintain body weight homeostasis.Key words: brainstem, adiposity, satiety.

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