Melanocortinergic Modulation of Cholecystokinin-Induced Suppression of Feeding through Extracellular Signal-Regulated Kinase Signaling in Rat Solitary Nucleus

Abstract Signals from the gut and hypothalamus converge in the caudal brainstem to control ingestive behavior. We have previously shown that phosphorylation of ERK1/2 in the solitary nucleus (NTS) is necessary for food intake suppression by exogenous cholecystokinin (CCK). Here we test whether this intracellular signaling cascade is also involved in the integration of melanocortin-receptor (MCR) mediated inputs to the caudal brainstem. Using fourth ventricular-cannulated rats and Western blotting of NTS tissue, we show that the MC4R agonist melanotan II (MTII) rapidly and dose-dependently increases phosphorylation of both ERK1/2 and cAMP response element-binding protein (CREB). Sequential administration of fourth ventricular MTII and peripheral CCK at doses that alone produced submaximal stimulation of pERK1/2 produced an additive increase. Prior fourth ventricular administration of the MC4R antagonist SHU9119 completely abolished the CCK-induced increases in pERK and pCREB and, in freely feeding rats, SHU9119 significantly increased meal size and satiety ratio. Prior administration of the MAPK kinase inhibitor U0126 abolished the capacity of MTII to suppress 2-h food intake and significantly decreased MTII-induced ERK phosphorylation in the NTS. Furthermore, pretreatment with the cAMP inhibitor, cAMP receptor protein-Rp isomer, significantly attenuated stimulation of pERK induced by either CCK or MTII. The results demonstrate that activation of the ERK pathway is necessary for peripheral CCK and central MTII to suppress food intake. The cAMP→ERK→CREB cascade may thus constitute a molecular integrator for converging satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake.

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The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)

Peptides ◽

10.1016/j.peptides.2005.01.025 ◽

2006 ◽

Vol 27 (2) ◽

pp. 259-264 ◽

Cited By ~ 69

Author(s):

Daniel L. Marks ◽

Victor Hruby ◽

Gregor Brookhart ◽

Roger D. Cone

Keyword(s):

Food Intake ◽

Melanocortin Receptor ◽

Selective Stimulation ◽

Type 3 ◽

Stimulation Of

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Meal patterns and hypothalamic NPY expression during chronic social stress and recovery

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00820.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. R813-R822 ◽

Cited By ~ 34

Author(s):

Susan J. Melhorn ◽

Eric G. Krause ◽

Karen A. Scott ◽

Marie R. Mooney ◽

Jeffrey D. Johnson ◽

...

Keyword(s):

Food Intake ◽

Social Stress ◽

Recovery Period ◽

Ingestive Behavior ◽

Meal Size ◽

Male Rats ◽

Dominant Male ◽

Mrna Levels ◽

Meal Patterns ◽

Chronic Social Stress

In the present study, we examined meal patterns during and after exposure to the visible burrow system (VBS), a rodent model of chronic social stress, to determine how the microstructure of food intake relates to the metabolic consequences of social subordination. Male Long-Evans rats were housed in mixed-sex VBS colonies (4 male, 2 female) for 2 wk, during which time a dominance hierarchy formed [1 dominant male (DOM) and 3 subordinate males (SUB)], and then male rats were individually housed for a 3-wk recovery period. Controls were individually housed with females during the 2-wk VBS period and had no changes in ingestive behavior compared with a habituation period. During the hierarchy-formation phase of VBS housing, DOM and SUB had a reduced meal frequency, whereas SUB also had a reduced meal size. However, during the hierarchy-maintenance phase of VBS housing, DOM meal patterns did not differ from controls, whereas SUB continued to display a reduced food intake via less frequent meals. During recovery, DOM had comparable meal patterns to controls, whereas SUB had an increased meal size. Hypothalamic neuropeptide Y (NPY) mRNA levels were not different between these groups during the experimental period. Together, the results suggest that exposure to chronic social stress alters ingestive behavior both acutely and in the long term, which may influence the metabolic changes that accompany bouts of stress and recovery; however, these differences in meal patterns do not appear to be mediated by hypothalamic NPY.

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NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00388.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. R1-R9 ◽

Cited By ~ 15

Author(s):

Carlos A. Campos ◽

Robert C. Ritter

Keyword(s):

Food Intake ◽

Glutamate Receptors ◽

Fourth Ventricle ◽

Neural Circuits ◽

Receptor Activation ◽

Meal Size ◽

Male Rats ◽

Melanocortin Receptor ◽

Cellular Mechanisms ◽

Nmdar Activation

Hindbrain injection of a melanocortin-3/4 receptor agonist, MTII, reduces food intake primarily by reducing meal size. Our previously reported results indicate that N-methyl-d-aspartate-type glutamate receptors (NMDAR) in the nucleus of the solitary tract (NTS) play an important role in the control of meal size and food intake. Therefore, we hypothesized that activation of NTS NMDARs contribute to reduction of food intake in response to fourth ventricle or NTS injection of MTII. We found that coinjection of a competitive NMDAR antagonist (d-CPP-ene) with MTII into the fourth ventricle or directly into the NTS of adult male rats attenuated MTII-induced reduction of food intake. Hindbrain NMDAR antagonism also attenuated MTII-induced ERK1/2 phosphorylation in NTS neurons and prevented synapsin I phosphorylation in central vagal afferent endings, both of which are cellular mechanisms previously shown to participate in hindbrain melanocortinergic reduction of food intake. Together, our results indicate that NMDAR activation significantly contributes to reduction of food intake following hindbrain melanocortin receptor activation, and it participates in melanocortinergic signaling in NTS neural circuits that mediate reduction of food intake.

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Nucleus accumbens GLP-1 receptors influence meal size and palatability

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00137.2013 ◽

2013 ◽

Vol 304 (12) ◽

pp. E1314-E1320 ◽

Cited By ~ 43

Author(s):

Amanda M. Dossat ◽

Ryan Diaz ◽

Lindsay Gallo ◽

Alyssa Panagos ◽

Kristen Kay ◽

...

Keyword(s):

Nucleus Accumbens ◽

Sucrose Solution ◽

Microstructural Analysis ◽

Lick Rate ◽

Ingestive Behavior ◽

Meal Size ◽

Nucleus Accumbens Core ◽

Glucagon Like Peptide 1 ◽

Stimulation Of ◽

Nutrient Infusion

Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control. To investigate the role of endogenous stimulation of GLP-1 receptors (GLP-1R) in NAcC, we examined the effects of the GLP-1R antagonist exendin-(9–39) (Ex9) on meal pattern and microstructure of ingestive behavior in rats. Intra-NAcC Ex9 treatment selectively increased meal size relative to vehicle in rats consuming 0.25 M sucrose solution or sweetened condensed milk. Microstructural analysis revealed effects of NAcC Ex9 on initial lick rate and the size and duration of licking bursts in rats consuming 0.1 or 0.25 M sucrose, suggesting that blockade of NAcC GLP-1R increases palatability. Because NAcC Ex9 did not affect licking for nonnutritive saccharin (0.1%), we suggest that the presence of nutrients in the gut may be required for endogenous stimulation of NAcC GLP-1R. Consistent with this, we also found that the meal size-suppressive effects of intragastric nutrient infusion were attenuated by NAcC delivery of Ex9 at a dose that had no effect when delivered alone. Analysis of licking patterns revealed that NAcC Ex9 did not reverse intragastric nutrient-induced suppression of burst number but rather blunted the effect of nutrient infusion on meal size primarily by increasing the size and duration of licking bursts. Together, our results suggest that NAcC Ex9 influences taste evaluation. We conclude that GLP-1 released in NAcC in response to gastrointestinal nutrients reduces the hedonic value of food.

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Peptide signals regulating food intake and energy homeostasis

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-035 ◽

2002 ◽

Vol 80 (5) ◽

pp. 396-406 ◽

Cited By ~ 34

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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CCK inhibits the orexigenic effect of peripheral ghrelin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00094.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. R751-R758 ◽

Cited By ~ 47

Author(s):

Peter Kobelt ◽

Johannes J. Tebbe ◽

Ines Tjandra ◽

Andreas Stengel ◽

Hi-Gung Bae ◽

...

Keyword(s):

Food Intake ◽

Neuronal Activity ◽

Arcuate Nucleus ◽

Ingestive Behavior ◽

Vehicle Group ◽

Reduce Food Intake ◽

Nonsignificant Trend ◽

Fos Expression ◽

Stimulation Of ◽

Cumulative Food Intake

CCK and ghrelin exert antagonistic effects on ingestive behavior. The aim of the present study was to investigate the interaction between ghrelin and CCK administered peripherally on food intake and neuronal activity in specific hypothalamic and brain stem nuclei, as assessed by c-Fos-like immunoreactivity (c-FLI) in nonfasted rats. Ghrelin (13 μg/kg body wt) injected intraperitoneally significantly increased the cumulative food intake when measured at 30 min and 1 h after injection, compared with the vehicle group (2.9 ± 1.0 g/kg body wt vs. 1.2 ± 0.5 g/kg body wt, P < 0.028). Sulfated CCK octapeptide (CCK-8S) (2 or 25 μg/kg body wt) injected simultaneously blocked the orexigenic effect of ghrelin (0.22 ± 0.13 g/kg body wt, P < 0.001 and 0.33 ± 0.23 g/kg body wt, P < 0.0008), while injected alone, both doses of CCK-8S exerted a nonsignificant trend to reduce food intake. Ghrelin (13 μg/kg body wt ip) markedly increased the number of c-FLI-positive neurons per section in the arcuate nucleus (ARC) compared with vehicle (median: 31.35 vs. 9.86, P < 0.0001). CCK-8S (2 or 25 μg/kg body wt ip) had no effect on neuronal activity in the ARC, as assessed by c-FLI (median: 5.33 and 11.21 cells per section), but blocked the ghrelin-induced increase of c- fos expression in this area when both peptides were administered simultaneously (median: 13.33 and 12.86 cells per section, respectively). Ghrelin at this dose had no effect on CCK-induced stimulation of c- fos expression in the paraventricular nucleus of the hypothalamus and the nucleus of the solitary tract. These results suggest that CCK abolishes ghrelin-induced food intake through dampening increased ARC neuronal activity.

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FAS inhibitor cerulenin reduces food intake and melanocortin receptor gene expression without modulating the other (an)orexigenic neuropeptides in chickens

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00899.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. R138-R147 ◽

Cited By ~ 27

Author(s):

Sami Dridi ◽

Cedric Ververken ◽

F. Bradley Hillgartner ◽

Arckens Lutgarde ◽

Estel Van der Gucht ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Food Intake ◽

Broiler Chickens ◽

Fatty Acid Synthase ◽

Ingestive Behavior ◽

The Other ◽

Melanocortin Receptor ◽

Synthetic Analog ◽

Mrna Levels

Cerulenin, a natural fatty acid synthase (FAS) inhibitor, and its synthetic analog C75 are hypothesized to alter the metabolism of neurons in the hypothalamus that regulate ingestive behavior to cause a profound decrease of food intake and an increase in metabolic rate, leading to body weight loss. The bulk of data exclusively originates from mammals (rodents); however, such effects are currently lacking in nonmammalian species. We have, therefore, addressed this issue in broiler chickens because this species is selected for high growth rate and high food intake and is prone to obesity. First, we demonstrate that FAS messenger and protein are expressed in the hypothalamus of chickens. FAS immunoreactivity was detected in a number of brain regions, including the nucleus paraventricularis magnocellularis and the nucleus infundibuli hypothalami, the avian equivalent of the mammalian arcuate nucleus, suggesting that FAS may be involved in the regulation of food intake. Second, we show that hypothalamic FAS gene expression was significantly ( P < 0.05) decreased by overnight fasting similar to that in liver, indicating that hypothalamic FAS gene is regulated by energy status in chickens. Finally, to investigate the physiological consequences of in vivo inhibition of fatty acid synthesis on food intake, we administered cerulenin by intravenous injections (15 mg/kg) to 2-wk-old broiler chickens. Cerulenin administration significantly reduced food intake by 23 to 34% ( P < 0.05 to P < 0.0001) and downregulated FAS and melanocortin receptors 1, 4, and 5 gene expression ( P < 0.05). However, the known orexigenic (neuropeptide Y, agouti gene-related peptide, orexin, and orexin receptor) and anorexigenic (pro-opiomelanocortin and corticotropin-releasing hormone) neuropeptide mRNA levels remained unchanged after cerulenin treatment. These results suggest that the catabolic effect of cerulenin in chickens may be mediated through the melanocortin system rather than the other neuropeptides known to be involved in food intake regulation.

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