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1.
eNeuro ; 11(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38806231

RESUMO

Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.


Assuntos
Dopamina , Núcleo Accumbens , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Masculino , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Ratos Sprague-Dawley , Gorduras na Dieta/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Agonistas dos Receptores da Amilina/farmacologia , Ratos , Sacarose/administração & dosagem , Sacarose/farmacologia
2.
J Endocrinol ; 262(1)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38642585

RESUMO

Binge eating is a central component of two clinical eating disorders: binge eating disorder and bulimia nervosa. However, the large treatment gap highlights the need to identify other strategies to decrease binge eating. Novel pharmacotherapies may be one such approach. Glucagon-like peptide-1 (GLP-1) is an intestinal and brain-derived neuroendocrine signal with a critical role in promoting glycemic control through its incretin effect. Additionally, the energy balance effects of GLP-1 are well-established; activation of the GLP-1 receptor (GLP-1R) reduces food intake and body weight. Aligned with these beneficial metabolic effects, there are GLP-1R agonists that are currently used for the treatment of diabetes and obesity. A growing body of literature suggests that GLP-1 may also play an important role in binge eating. Dysregulation of the endogenous GLP-1 system is associated with binge eating in non-human animal models, and GLP-1R agonists may be a promising approach to suppress the overconsumption that occurs during binge eating. Here, we briefly discuss the role of GLP-1 in normal energy intake and reward and then review the emerging evidence suggesting that disruptions to GLP-1 signaling are associated with binge eating. We also consider the potential utility of GLP-1-based pharmacotherapies for reducing binge eating behavior.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Animais , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Transtorno da Compulsão Alimentar/tratamento farmacológico , Transtorno da Compulsão Alimentar/metabolismo , Bulimia/metabolismo , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia
3.
Peptides ; 176: 171197, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38493922

RESUMO

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.


Assuntos
Comportamento Alimentar , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Animais , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Ratos , Comportamento Alimentar/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ratos Sprague-Dawley , Peso Corporal/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos
4.
Pharmacol Biochem Behav ; 237: 173723, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331049

RESUMO

Obesity is a prevalent disease, but effective treatment options remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that central administration of the α7nAChR agonist PHA-543613 (PHA) would decrease food intake and body weight in adult male Sprague Dawley rats. Intracerebroventricular (ICV) PHA administration in chow-fed rats produced a suppression of energy intake and weight gain over 24 h. Next, to evaluate effects of ICV PHA on palatable food intake, rats were maintained on a choice diet of rodent chow and 45 % high fat diet (HFD); under these conditions, ICV PHA produced no significant changes in energy intake from either food, or body weight gain, in the 24 h post-injection. However, when given a choice of chow or a higher-fat 60 % HFD, ICV PHA reduced intake of 60 % HFD, but not chow; body weight gain was also suppressed. Further experiments evaluating conditioned taste avoidance (CTA) and pica in response to ICV PHA suggested that the suppressive food intake and body weight effects after ICV injection of PHA were not due to nausea/malaise. Finally, an operant conditioning study showed that responding on a progressive ratio schedule of reinforcement for high-fat food pellets decreased after ICV PHA. Collectively, these studies show that PHA reduces energy intake under some but not all dietary conditions. Importantly, central PHA decreases both food intake as well as motivation for highly palatable, energy dense foods in rats without inducing nausea/malaise, suggesting that the α7nAChR could be a viable target for developing treatments for obesity.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Ingestão de Alimentos , Quinuclidinas , Receptor Nicotínico de Acetilcolina alfa7 , Ratos , Camundongos , Masculino , Animais , Ratos Sprague-Dawley , Obesidade , Aumento de Peso , Peso Corporal , Náusea
5.
Appetite ; 180: 106365, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36347305

RESUMO

A plethora of studies to date has examined the roles of feeding-related peptides in the control of food intake. However, the influence of these peptides on the intake of particular macronutrient constituents of food - carbohydrate, fat, and protein - has not been as extensively addressed in the literature. Here, the roles of several feeding-related peptides in controlling macronutrient intake are reviewed. Next, the relationship between macronutrient intake and diseases including diabetes mellitus, obesity, and eating disorders are examined. Finally, some key considerations in macronutrient intake research are discussed. We hope that this review will shed light onto this underappreciated topic in ingestive behavior research and will help to guide further scientific investigation in this area.


Assuntos
Ingestão de Alimentos , Peptídeos , Humanos
6.
Pharmacol Biochem Behav ; 219: 173444, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35944617

RESUMO

Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Compostos de Benzilideno , Peso Corporal , Ingestão de Alimentos , Masculino , Camundongos , Piridinas , Ratos , Ratos Sprague-Dawley , Receptor Nicotínico de Acetilcolina alfa7/agonistas
7.
Behav Brain Res ; 428: 113869, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35378108

RESUMO

Binge eating involves consumption of large amounts of food and a loss of control over the amount consumed. The incidence of binge eating disorder is higher in females than males, hinting at important sex differences in binge eating behavior, but the neural underpinnings of binge eating still remain unresolved. Recent work in male rats has shown that a history of binge-like palatable food intake suppresses hindbrain expression of preproglucagon (PPG), the precursor for glucagon-like peptide-1 (GLP-1). Given the roles of GLP-1 in reducing feeding and food reward, this could be a mechanism underlying binge-like eating in rodents. However, whether similar effects occur in female rats is unknown. Here, we tested the hypothesis that a history of binge-like palatable food intake in female rats would reduce PPG expression in the nucleus tractus solitarius (NTS), a key central site of GLP-1 production. Female rats given access to vegetable shortening every fourth day (4D) engaged in binge-like feeding, demonstrated by consuming significantly more shortening during the first hour of fat access compared to counterparts with ad libitum (AL) fat access. After several weeks of fat access under these schedules, PPG and GLP-1 receptor (GLP-1R) expression were measured in the NTS and ileum. Surprisingly, and in contrast to previous findings in male rats, there were no significant differences in expression of PPG or GLP-1R in either site in 4D versus AL rats, nor were there effects on plasma GLP-1 levels. These findings highlight key differences in the effects of binge-like intake on the central GLP-1 system in female compared to male rats.


Assuntos
Transtorno da Compulsão Alimentar , Peptídeo 1 Semelhante ao Glucagon , Animais , Transtorno da Compulsão Alimentar/metabolismo , Ingestão de Alimentos , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo
8.
Physiol Behav ; 240: 113541, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34332974

RESUMO

Amylin is a peptide hormone involved in the control of energy balance, making the amylin system a potential target for pharmacotherapies to treat obesity. Pramlintide, an amylin analogue, is an FDA-approved medication for the treatment of diabetes that also has food intake- and body weight-suppressive effects. However, it is unknown whether pramlintide may preferentially reduce intake of highly palatable, energy dense food, the overconsumption of which is thought to play a role in the etiology of obesity. Here, we investigate the effects of pramlintide on food intake and body weight in rats given a choice of chow and high fat diet (HFD). Systemic pramlintide injection in rats reduced HFD intake at 3h post-injection, with no effects at other times and no significant effects on chow intake, body weight, or percent preference for HFD. In a separate experiment, the effects of central injection of pramlintide on food intake and body weight were similarly evaluated. Intracerebroventricular pramlintide significantly reduced HFD intake throughout the 24h post-injection, with some suppressive effects on chow intake, and also decreased 24h body weight change. Again, no significant changes were observed in the proportion of calories obtained from HFD. The same intracerebroventricular doses of pramlintide did not induce pica, suggesting that pramlintide-mediated reductions in feeding are not due to nausea/malaise. Our results suggest that pramlintide reduces food intake in rats largely via reductions in intake of HFD versus chow, supporting the idea that the potent effects of pramlintide on palatable food intake may have utility in the treatment of obesity.


Assuntos
Preferências Alimentares , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Animais , Dieta Hiperlipídica , Ingestão de Energia , Ratos
9.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R250-R259, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34259025

RESUMO

The peptide hormone amylin reduces food intake and body weight and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds' potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration. Acute dose-response studies indicate that systemic ZP5461 (0.5-3 nmol/kg) robustly suppresses energy intake and body weight gain in chow- and high-fat diet (HFD)-fed rats. When HFD-fed rats received chronic systemic administration of ZP5461 (1-2 nmol/kg), the compound initially produced reductions in energy intake and weight gain but failed to produce sustained suppression of intake and body weight. Using virally mediated knockdown of DVC CTRs, the ability of chronic systemic ZP5461 to promote early reductions in intake and body weight gain was determined to be mediated in part by activation of DVC CTRs, implicating the DVC as a central site of action for ZP5461. Future studies should address other dosing regimens of ZP5461 to determine whether an alternative dose/frequency of administration would produce more sustained body weight suppression.


Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Receptores da Calcitonina/agonistas , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/efeitos dos fármacos , Rombencéfalo/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Ingestão de Energia/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/genética , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Rombencéfalo/metabolismo , Transdução de Sinais , Fatores de Tempo , Nervo Vago/metabolismo
10.
Horm Behav ; 134: 105017, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34174584

RESUMO

It is well known that stress elevates intake of total calories and shifts food preference toward unhealthy food choices. There is, however, little known on the physiological mechanisms that drive stress-induced hyperphagia. In order to better understand how to reduce stress eating, it is critical to identify mechanisms in humans that are points of convergence between stress and eating. The feeding-related hormones ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and amylin are likely candidates. It was hypothesized that ghrelin, an orexigenic hormone, would increase in response to an acute laboratory stressor, but that leptin, GLP-1, and amylin (anorexigenic hormones) would decrease after stress. To this aim, participants (n = 47) came into the laboratory and had feeding-related hormones, salivary cortisol and α-amylase, and self-rated anxiety measured. Then they underwent either exposure to a stressor (n = 24), which reliably elevates measures of stress and energy intake, or a no-stress condition (n = 23). Feeding hormones, stress hormones, and self-rated anxiety were measured twice more after the stressor. Elevated self-rated anxiety and α-amylase confirmed the validity of the stressor. Furthermore, there was a time X condition interaction for both ghrelin and GLP-1. Ghrelin was significantly elevated after stress compared to baseline (p = .02) and there was a trend for GLP-1 to be higher in the stress condition over the no-stress condition immediately after the stressor (p = .07). Overall, ghrelin is the most likely candidate driving energy intake after stress in humans.


Assuntos
Grelina , Leptina , Ingestão de Energia , Feminino , Peptídeo 1 Semelhante ao Glucagon , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino
11.
Physiol Behav ; 236: 113418, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838203

RESUMO

Maintaining fluid balance is critical for life. The central components that control fluid intake are only partly understood. This contribution to the collection of papers highlighting work by members of the Society for the Study of Ingestive Behavior focuses on the role that dopamine has on fluid intake and describes the roles that various bioregulators can have on thirst and sodium appetite by influencing dopamine systems in the brain. The goal of the review is to highlight areas in need of more research and to propose a framework to guide that research. We hope that this framework will inspire researchers in the field to investigate these interesting questions in order to form a more complete understanding of how fluid intake is controlled.


Assuntos
Dopamina , Sódio na Dieta , Angiotensina II , Apetite , Ingestão de Líquidos , Sede , Equilíbrio Hidroeletrolítico
12.
Physiol Behav ; 232: 113350, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33548222

RESUMO

We tested the hypothesis that cool-seeking behavior during heat exposure is attenuated when physical effort is required. Twelve healthy adults (mean(SD), 24(4) years, four women) underwent three experimental trials during two hours of exposure to 41(1) °C, 20(0)% relative humidity in which subjects undertook intermittent exercise alternating between seated rest and cycling exercise at ~4 metabolic equivalents every 15 min. In all trials, subjects wore a water perfused suit top. In the control trial (Control), no water perfused the suit. In the other trials, subjects were freely able to perfuse 2.1(0.2) °C water through the suit. In one cooling trial, subjects received two minutes of cooling by pressing a button (Button). The other cooling trial permitted cooling by engaging in isometric handgrip exercise at 15% of maximal grip strength (Handgrip), with cooling maintained throughout the duration the required force was produced or until two minutes elapsed. In both Button and Handgrip, a one-minute washout proceeded cooling. Core temperature increased over time in all trials (P<0.01) and there were no differences between trials (P = 0.32). Mean skin temperature at the end of heat exposure was lowest in Button [34.2(1.5) °C] compared to Handgrip [35.6(0.8) °C, P = 0.03] and Control [36.9(0.7) °C, P<0.01]. The total number of behaviors [8(3) vs. 10(5), P = 0.04] and cumulative cooling time [850(323) vs. 1230(616) seconds, P = 0.02] were lower in Handgrip compared to Button. These data indicate that when physical effort is required, the incidence and duration of cooling behavior during heat exposure is attenuated compared to when behaving requires minimal physical effort.


Assuntos
Temperatura Alta , Esforço Físico , Adulto , Temperatura Corporal , Regulação da Temperatura Corporal , Temperatura Baixa , Feminino , Força da Mão , Humanos
13.
Physiol Behav ; 222: 112958, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32439326

RESUMO

The intake- and body weight-suppressive hormone amylin exerts effects on energy balance control at a variety of nuclei within the brain, including sites that have been referred to in the literature as mediating homeostatic versus hedonic aspects of feeding. Here, we review key central nervous system sites of action for amylin signaling in the neural control of feeding and body weight, and discuss how these sites may interact to mediate the effects of amylin within the brain. Additionally, we review recent findings suggesting that amylin influences alcohol intake, suggesting broader effects of amylin on motivated behavior beyond feeding.


Assuntos
Metabolismo Energético , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Peso Corporal , Ingestão de Alimentos , Humanos , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Transdução de Sinais
14.
Exp Physiol ; 105(6): 1012-1024, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32306457

RESUMO

NEW FINDINGS: What is the central question of this study? We tested whether intra-nucleus accumbens core amylin receptor (AmyR) activation suppresses feeding and evaluated whether intake of palatable food influences mesocorticolimbic AmyR expression. What is the main finding and its importance? Intra-nucleus accumbens core AmyR activation reduces food intake in some dietary conditions. We showed that all components of the AmyR are expressed in the prefrontal cortex and central nucleus of the amygdala and demonstrated that access to fat impacts AmyR expression in these and other mesocorticolimbic nuclei. These results suggest that the intake of palatable food might alter amylin signalling in the brain and shed further light onto potential sites of action for amylin. ABSTRACT: Amylin is a pancreas- and brain-derived peptide that acts within the CNS to promote negative energy balance. However, our understanding of the CNS sites of action for amylin remains incomplete. Here, we investigate the effect of amylin receptor (AmyR) activation in the nucleus accumbens core (NAcC) on the intake of bland and palatable foods. Intra-NAcC injection of the AmyR agonist salmon calcitonin or amylin itself in male chow-fed rats had no effect on food intake, meal size or number of meals. However, in chow-fed rats with access to fat solution, although fat intake was not affected by intra-NAcC AmyR activation, subsequent chow intake was suppressed. Given that mesolimbic AmyR activation suppresses energy intake in rats with access to fat solution, we tested whether fat access changes AmyR expression in key mesocorticolimbic nuclei. Fat exposure did not affect NAcC AmyR expression, whereas in the accumbens shell, expression of receptor activity modifying protein (RAMP) 3 was significantly reduced in fat-consuming rats. We show that all components of AmyRs are expressed in the medial prefrontal cortex and central nucleus of the amygdala; fat access significantly reduced expression of calcitonin receptor-A in the central nucleus of the amygdala and RAMP2 in the medial prefrontal cortex. Taken together, these results indicate that intra-NAcC AmyR activation can suppress energy intake and, furthermore, suggest that AmyR signalling in a broader range of mesocorticolimbic sites might have a role in mediating the effects of amylin on food intake and body weight.


Assuntos
Ingestão de Alimentos/fisiologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/fisiologia , Agonistas dos Receptores da Amilina/farmacologia , Animais , Calcitonina/farmacologia , Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Masculino , Ratos , Ratos Sprague-Dawley
15.
Physiol Behav ; 219: 112830, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061682

RESUMO

Binge eating involves eating larger than normal quantities of food within a discrete period of time. The neurohormonal controls governing binge-like palatable food intake are not well understood. Glucagon-like peptide-1 (GLP-1), a hormone produced peripherally in the intestine and centrally in the nucleus tractus solitarius (NTS), reduces food intake. Given that the NTS plays a critical role in integrating peripheral and central signals relevant for food intake, as well as the role of GLP-1 in motivated feeding, we tested the hypothesis that expression of the GLP-1 precursor preproglucagon (PPG) would be reduced in the NTS of rats with a history of binge-like palatable food intake. Adult male rats received access to fat for 1 h shortly before lights off, either every day (Daily, D) or only 3d/week (Intermittent, INT). INT rats ate significantly more fat than did D rats in sessions where all rats had fat access. After ~8.5 weeks of diet maintenance, we measured plasma GLP-1 as well as NTS PPG and GLP-1 receptor expression. INT rats had significantly lower NTS PPG mRNA expression compared to D rats. However, plasma GLP-1 was significantly increased in the INT group versus D rats. No significant differences were observed in NTS GLP-1 receptor expression. We also measured plasma insulin levels, fasted blood glucose, and plasma corticosterone but no differences were detected between groups. These results support the hypothesis that binge-like eating reduces NTS GLP-1 expression, and furthermore, demonstrate divergent impacts of binge-like eating on peripheral (plasma) versus central GLP-1.


Assuntos
Transtorno da Compulsão Alimentar , Núcleo Solitário , Animais , Ingestão de Alimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Proglucagon/genética , Ratos , Núcleo Solitário/metabolismo
17.
Physiol Behav ; 194: 545-551, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30017641

RESUMO

We tested the hypothesis that the motivation to behaviorally thermoregulate in humans is dependent on the magnitude of changes in mean skin temperature. Ten healthy subjects (22 ±â€¯3 y, 5 females) underwent 60 min of seated rest in a 32±1 °C or 42±1 °C environment (20% relative humidity). Trials were completed in a counterbalanced order. The motivation to behaviorally thermoregulate was measured using an operant behavior task on a fixed ratio schedule, in which subjects received thermal reinforcement after clicking a button 100 times. The reinforcer was 30 s of cooling on the dorsal aspect of the neck. The motivation to behave was defined as the cumulative number of button clicks over time and behavioral thermoregulation was defined as the change in neck skin temperature. Mean skin temperature was higher throughout the 42 °C versus the 32 °C trial (at 60 min: 36.3±0.5 °C vs. 34.5±0.5 °C, P < .01) and core temperature became higher in this trial 40 min into heat exposure (at 60 min: 37.2±0.2 °C vs. 37.1±0.1 °C, P ≤ .04), but did not differ from pre- heat exposure (P = .81). Neck skin temperature was lower in the 42 °C compared to the 32 °C trial starting at 30 min (33.7±0.8 °C vs. 35.3±0.5°C, P < .01), which was maintained thereafter (P ≤ .04). Cumulative responding for thermal reinforcement was greater in the 42 °C trial compared to the 32 °C trial at 20 min (180±155 clicks vs. 0±0 clicks, P < .01), which persisted thereafter (P < .01). These data indicate that the motivation to behaviorally thermoregulate during passive heat exposure in humans is dependent on the magnitude of increases in skin temperature.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Temperatura Alta , Motivação/fisiologia , Temperatura Cutânea/fisiologia , Condicionamento Operante , Feminino , Humanos , Masculino , Esquema de Reforço , Adulto Jovem
18.
Neuropsychopharmacology ; 43(10): 2000-2008, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29497166

RESUMO

Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9-39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA reduced cocaine seeking. Finally, extinction following cocaine self-administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Comportamento de Procura de Droga/efeitos dos fármacos , Exenatida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Exenatida/administração & dosagem , Exenatida/farmacocinética , Masculino , Neurônios/efeitos dos fármacos , Proglucagon/biossíntese , Proglucagon/genética , Ratos , Ratos Sprague-Dawley , Recidiva , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo
19.
Diabetes Obes Metab ; 20(5): 1223-1234, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29327400

RESUMO

AIMS: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise. MATERIALS AND METHODS: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined. RESULTS: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4. CONCLUSION: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.


Assuntos
Regulação do Apetite/efeitos dos fármacos , Exenatida/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Vitamina B 12/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Estabilidade de Medicamentos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Exenatida/efeitos adversos , Exenatida/farmacocinética , Exenatida/uso terapêutico , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Células HEK293 , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos Endogâmicos C57BL , Náusea/induzido quimicamente , Náusea/prevenção & controle , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Distribuição Tecidual , Vitamina B 12/efeitos adversos , Vitamina B 12/farmacocinética , Vitamina B 12/uso terapêutico
20.
Neuropsychopharmacology ; 43(3): 627-637, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28920591

RESUMO

The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding.


Assuntos
Ingestão de Alimentos/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Tegmento Mesencefálico/metabolismo , Animais , Fármacos do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Exenatida , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Masculino , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Ratos Sprague-Dawley , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Tegmento Mesencefálico/citologia , Tegmento Mesencefálico/efeitos dos fármacos , Peçonhas/farmacologia
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