Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice

1993 ◽  
Vol 265 (3) ◽  
pp. R481-R486 ◽  
Author(s):  
Y. Hirosue ◽  
A. Inui ◽  
A. Teranishi ◽  
M. Miura ◽  
M. Nakajima ◽  
...  
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Rank Order ◽  
Peripheral Circulation ◽  
Inhibitory Effect ◽  
Peripheral Tissues ◽  
Cholecystokinin Octapeptide ◽  
The Central Nervous System ◽  
The Difference ◽  
The Brain

To examine the mechanism of the satiety-producing effect of cholecystokinin (CCK) in the central nervous system, we compared the potency of intraperitoneally (ip) or intracerebroventricularly (icv) administered CCK-8 and its analogues on food intake in fasted mice. The icv administration of a small dose of CCK-8 (0.03 nmol/brain) or of Suc-(Thr28, Leu29, MePhe33)-CCK-7 (0.001 nmol/brain) suppressed food intake for 20 min, whereas CCK-8 (1 nmol/kg, which is equivalent to 0.03 nmol/brain) or Suc-(Thr28, Leu29, MePhe33)-CCK-7 (1 nmol/kg) had satiety effect after ip administration. Dose-response studies indicated the following rank order of potency: Suc-CCK-7 > or = Suc-(Thr28, Leu29, MePhe33)-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of ip administration and Suc-(Thr28, Leu29, MePhe33)-CCK-7 >> Suc-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of icv administration. The selective CCK-A receptor antagonist MK-329 reversed the inhibitory effect of the centrally as well as peripherally administered CCK-8, or of Suc-(Thr28, Leu29, MePhe33)-CCK-7, whereas the selective CCK-B receptor antagonist L-365260 did not. The icv administered CCK-8 did not appear in the peripheral circulation. These findings suggest the participation of CCK-A receptors in the brain in mediating the satiety effect of CCK and the difference in CCK-A receptors in the brain and peripheral tissues.

scholarly journals Peripheral Spexin Inhibited Food Intake in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shuangyu Lv ◽  
Yuchen Zhou ◽  
Yu Feng ◽  
Xiaomei Zhang ◽  
Xinyue Wang ◽  
...  
Keyword(s):  
Food Intake ◽  
Dark Period ◽  
Mrna Level ◽  
Inhibitory Effect ◽  
Appetite Regulation ◽  
Peripheral Tissues ◽  
Anorectic Effect ◽  
The Central Nervous System ◽  
Cumulative Food Intake

Spexin (SPX, NPQ), a novel endogenous neuropeptide, was firstly identified by bioinformatics. Spexin gene and protein widely distributed in the central nervous system and peripheral tissues, such as the hypothalamus and digestive tract. The role of spexin in appetite regulation in mammalian is still unclear. The present study was designed to investigate the mechanism and effect of peripheral spexin on food intake in mice. During the light period, an intraperitoneal (i.p.) injection of spexin (10 nmol/mouse) significantly inhibited cumulative food intake at 2, 4, and 6 h after treatment in fasted mice. During the dark period, spexin (1 and 10 nmol/mouse, i.p.) significantly suppressed cumulative food intake at 4 and 6 h after treatment in freely feeding mice. The GALR3 antagonist SNAP37889, not GALR2 antagonist, significantly antagonized the inhibitory effect on cumulative food intake (0–6 h) induced by spexin. Spexin significantly reduced the mRNA level of Npy mRNA, not Agrp, Pomc, Cart, Crh, Orexin, or Mch, in the hypothalamus. Spexin (10 nmol/mouse, i.p.) increased the number of c-Fos positive neurons in hypothalamic AHA and SCN, but not in ARC, DMN, LHA, PVN, SON, or VMH. The hypothalamic p-CaMK2 protein expression was upregulated by spexin. This study indicated that acute peripheral injection of spexin inhibited mouse food intake. The anorectic effect may be mediated by GALR3, and inhibiting neuropeptide Y (NPY) via p-CaMK2 and c-Fos in the hypothalamus.

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

scholarly journals Expression of urocortin in rat lung and its effect on pulmonary vascular permeability

2006 ◽  
Vol 189 (1) ◽  
pp. 167-178 ◽  
Author(s):  
Yuqing Wu ◽  
Yinyan Xu ◽  
Hong Zhou ◽  
Jin Tao ◽  
Shengnan Li
Keyword(s):  
Receptor Antagonist ◽  
Vascular Permeability ◽  
Alveolar Epithelium ◽  
Bronchial Epithelium ◽  
Rat Lung ◽  
Pulmonary Vascular Permeability ◽  
Peripheral Tissues ◽  
The Central Nervous System ◽  
Hematoxylin And Eosin ◽  
Lung Vascular Permeability

Urocortin (UCN), a newly identified, 40-amino-acid, corticotropin-releasing hormone (CRH) structurally related peptide, has been demonstrated to be expressed in the central nervous system and many peripheral tissues of rats and man. This study aimed to investigate the expression profile of UCN in rat lung and the effect of UCN on lung vascular permeability. The expression of UCN mRNA was detected by reverse transcriptase PCR (RT–PCR). UCN peptide was measured by immunohistochemistry and Western blot analysis. We found that both UCN mRNA and peptide were obviously expressed in rat lung. Immunohistochemistry results showed that UCN peptide is mainly expressed in bronchial epithelium mucosa and alveolar epithelium. We also found that rats receiving inhalation aerosol of UCN had a significant elevation of lung vascular permeability compared with rats receiving vehicle and ovalbumin (OVA) by the Evans blue (EB) technique. UCN aerosol inhalation resulted in obvious pulmonary congestion and edema observed under light microscope by hematoxylin and eosin (HE) staining. The nonselective peptide CRH receptor antagonist astressin markedly reduced lung vascular permeability triggered by UCN. Enhanced pulmonary vascular permeability induced by UCN was markedly inhibited by pretreatment with the mast-cell stabilizer cromolyn and histamine-1 (H1) receptor antagonist azelastine respectively, but not by the leukotriene receptor antagonist montelukast. In summary, in the present study, we demonstrated for the first time that UCN is expressed in rat lung and contributes to an increase in lung vascular permeability through activation of CRH receptors. Mast cells and histamine may be involved in this effect of UCN. Peripherally produced UCN in lung may act as an autocrine and paracrine proinflammatory factor.

Capsaicin attenuates hindbrain neuron responses to circulating cholecystokinin

1989 ◽  
Vol 257 (5) ◽  
pp. R1162-R1168 ◽  
Author(s):  
R. C. Ritter ◽  
S. Ritter ◽  
W. R. Ewart ◽  
D. L. Wingate
Keyword(s):  
Food Intake ◽  
Sensory Neurons ◽  
Gastric Distension ◽  
Extracellular Recordings ◽  
Cholecystokinin Octapeptide ◽  
Unmyelinated Axons ◽  
Sensory Modalities ◽  
Afferent Inputs ◽  
Dorsal Hindbrain ◽  
The Brain

Capsaicin is a neurotoxin that destroys small sensory neurons with unmyelinated axons, including a subpopulation of vagal sensory neurons. Capsaicin treatment attenuates suppression of food intake induced by systemic administration of cholecystokinin (CCK) but not by gastric distension. However, both gastric distension and intravascular CCK alter the discharge of dorsal hindbrain neurons by a vagal mechanism. Therefore, it is plausible that some hindbrain neurons receive convergent input from capsaicin-sensitive vagal neurons that are responsive to CCK and also from capsaicin-insensitive neurons that are responsive to gastric distension. To investigate this possibility we made extracellular recordings from gastric distension-responsive hindbrain neurons during intra-arterial cholecystokinin octapeptide (CCK-8) administration in anesthetized intact and capsaicin-pretreated rats. We found that capsaicin-pretreated rats exhibit attenuated neuronal discharge responses to CCK-8 but not to gastric distension. These results are consistent with the existence of convergent CCK-sensitive and gastric distension-sensitive afferent inputs to hindbrain neurons and suggest that various gastrointestinal sensory modalities may be communicated to the brain by populations of neurons that can be distinguished by their sensitivity to neurotoxins.

Central nervous control of voluntary food intake

1989 ◽  
Vol 13 ◽  
pp. 7-26 ◽  
Author(s):  
J. M. Forbes ◽  
J. E. Blundell
Keyword(s):  
Nervous System ◽  
Food Intake ◽  
Peptide Yy ◽  
Blood Stream ◽  
Vital Role ◽  
Nervous Control ◽  
Electrolytic Lesions ◽  
The Central Nervous System ◽  
The Brain ◽  
Voluntary Food Intake

AbstractThe central nervous system is the integrator of most of the actions of the animal and as such plays a vital rôle in the control of voluntary food intake. Much of the work to understand how intake is controlled has been carried out with rats but that which has been done with pigs is included. The first experiments used electrolytic lesions in the designation of the ‘hunger centre’ and the ‘satiety centre’. Recent work has identified the paraventricular nucleus as a sensing site for experimental manipulations. Chemical stimulation of the brain has also been carried out to try to gain understanding of the rôle of neurotransmitters. Noradrenaline (NA) stimulates intake when given into many sites. Serotonin (5-HT) inhibits intake and has been claimed to play a rôle in the selection of macronutrients but 5-HT must now be interpreted in the light of the existence of several different subtypes of 5-HT receptors. Dopamine appears to moderate the hedonic response of eating. Numerous peptides are active in the brain where their rôle as neuromodulators may be quite different from their function in the periphery and at least three types of opioid receptors are implicated with kappa antagonists producing the most potent facilitatory effects. Neuropeptide Y and peptide YY produce massive orexigenic effects which readily overcome peripheral satiety factors. The brain cannot control intake in isolation. It receives inputs in the blood stream, such as glucose, as well as via the nervous system, both from the special senses and from visceral organs such as stomach, intestines and liver. Taste and olfaction are important in diet selection and a specific appetite for protein has been demonstrated in the pig.

scholarly journals Preproglucagon neurons in the hindbrain have IL-6 receptor-α and show Ca2+ influx in response to IL-6

2016 ◽  
Vol 311 (1) ◽  
pp. R115-R123 ◽  
Author(s):  
Fredrik Anesten ◽  
Marie K. Holt ◽  
Erik Schéle ◽  
Vilborg Pálsdóttir ◽  
Frank Reimann ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Food Intake ◽  
Extracellular Space ◽  
Solitary Tract ◽  
Neuronal Marker ◽  
Reporter Mice ◽  
The Central Nervous System ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

Neuronal circuits in the hypothalamus and hindbrain are of importance for control of food intake, energy expenditure, and fat mass. We have recently shown that treatment with exendin-4 (Ex-4), an analog of the proglucagon-derived molecule glucagon-like peptide 1 (GLP-1), markedly increases mRNA expression of the cytokine interleukin-6 (IL-6) in the hypothalamus and hindbrain and that this increase partly mediates the suppression of food intake and body weight by Ex-4. Endogenous GLP-1 in the central nervous system (CNS) is produced by preproglucagon (PPG) neurons of the nucleus of the solitary tract (NTS) in the hindbrain. These neurons project to various parts of the brain, including the hypothalamus. Outside the brain, IL-6 stimulates GLP-1 secretion from the gut and pancreas. In this study, we aim to investigate whether IL-6 can affect GLP-1-producing PPG neurons in the nucleus of the solitary tract (NTS) in mouse hindbrain via the ligand binding part of the IL-6 receptor, IL-6 receptor-α (IL-6Rα). Using immunohistochemistry, we found that IL-6Rα was localized on PPG neurons of the NTS. Recordings of these neurons in GCaMP3/GLP-1 reporter mice showed that IL-6 enhances cytosolic Ca2+ concentration in neurons capable of expressing PPG. We also show that the Ca2+ increase originates from the extracellular space. Furthermore, we found that IL-6Rα was localized on cells in the caudal hindbrain expressing immunoreactive NeuN (a neuronal marker) or CNP:ase (an oligodendrocyte marker). In summary, IL-6Rα is present on PPG neurons in the NTS, and IL-6 can stimulate these cells by increasing influx of Ca2+ to the cytosol from the extracellular space.

scholarly journals Brain HIV-1 latently-infected reservoirs targeted by the suicide gene strategy

2020 ◽  
Author(s):  
Sepideh Saeb ◽  
Mehrdad Ravanshad ◽  
Mahmoud Reza Pourkarim ◽  
Fadoua Daouad ◽  
Kazem Baesi ◽  
...  
Keyword(s):  
Suicide Gene ◽  
Microglial Cells ◽  
Peripheral Tissues ◽  
Latently Infected ◽  
Shock And Kill ◽  
The Central Nervous System ◽  
Infected Cells ◽  
Set Up ◽  
The Brain ◽  
Hiv 1

Abstract Several strategies are currently investigated to reduce the pool of all HIV-1 reservoirs in infected patients in order to achieve functional cure. The most prominent HIV-1 cell reservoirs in the brain are microglial cells. Virus infection maybe lifelong. Infected microglial cells are believed to be the source of peripheral tissues reseeding and responsible for the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system prevent the eradication of brain reservoirs. Current trials, such as “shock and kill”, the “deep and lock” and the gene editing strategies do not respond to these difficulties. Therefore, new strategies have to be designed when considering brain reservoirs such as microglial cells. We set up an original gene suicide strategy using a latently infected microglial model. In this paper we provide proof of concept of this strategy. Our results demonstrate that this strategy enables the eradication of latently-infected microglial cells.

INHIBITION AND FACILITATION OF FEEDBACK INFLUENCES OF DEXAMETHASONE ON ADRENOCORTICAL RESPONSES TO ETHER STRESS IN RATS WITH HYPOTHALAMIC DEAFFERENTATIONS AND BRAIN LESIONS

1976 ◽  
Vol 82 (4) ◽  
pp. 785-791 ◽  
Author(s):  
Shaul Feldman ◽  
Nissim Conforti
Keyword(s):  
Negative Feedback ◽  
Medial Forebrain Bundle ◽  
Inhibitory Effect ◽  
Brain Lesions ◽  
The Difference ◽  
Sites Of Action ◽  
Bilateral Lesions ◽  
Adrenocortical Responses ◽  
The Brain ◽  
Intact Rats

ABSTRACT In order to elucidate the mechanisms and the sites of action of the negative feedback of corticoids in the regulation of ACTH secretion, the effects of systemically administered dexamethasone on adrenocortical responses to ether stress were studied in intact rats and in 11 experimental groups. These included animals with partial anterior, anterolateral, posterolateral, posterior and small posterior deafferentations as well as bilateral lesions in the medial forebrain bundle (MFB), fasciculus longitudinalis dorsalis (FLD), medial and lateral midbrain reticular formation (MRF) and in the ventrolateral pons. In rats with posterior hypothalamic deafferentation the degree of the inhibitory effect of dexamethasone was much smaller than that in intact animals. In animals with lesions in the FLD and MRF, dexamethasone also produced a reduction in the suppression of the response, though the difference was not significant. Bilateral lesions in the MFB and MP have on the other hand very significantly enhanced the effect of the negative feedback of dexamethasone when compared to intact rats. These data would indicate that hypothalamic deafferentations and brain lesions may change the sensitivity of the hypothalamus for the feedback control of corticoids and that there exist two antagonistic systems, an inhibitory and a facilitatory, in the brain which mediate this effect.

scholarly journals Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood–Brain Barrier

2019 ◽  
Vol 20 (21) ◽  
pp. 5393 ◽  
Author(s):  
Herold ◽  
Schroten ◽  
Schwerk
Keyword(s):  
Blood Brain Barrier ◽  
Virulence Factors ◽  
Host Cells ◽  
Brain Barrier ◽  
Host Cell Signaling ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Difference ◽  
Multiple Pathogens ◽  
The Brain

Infections of the central nervous system (CNS) are still a major cause of morbidity and mortality worldwide. Traversal of the barriers protecting the brain by pathogens is a prerequisite for the development of meningitis. Bacteria have developed a variety of different strategies to cross these barriers and reach the CNS. To this end, they use a variety of different virulence factors that enable them to attach to and traverse these barriers. These virulence factors mediate adhesion to and invasion into host cells, intracellular survival, induction of host cell signaling and inflammatory response, and affect barrier function. While some of these mechanisms differ, others are shared by multiple pathogens. Further understanding of these processes, with special emphasis on the difference between the blood–brain barrier and the blood–cerebrospinal fluid barrier, as well as virulence factors used by the pathogens, is still needed.

scholarly journals Amylin Acts in the Central Nervous System to Increase Sympathetic Nerve Activity

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2481-2488 ◽  
Author(s):  
Caroline Fernandes-Santos ◽  
Zhongming Zhang ◽  
Donald A. Morgan ◽  
Deng-Fu Guo ◽  
Andrew F. Russo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Food Intake ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Nerve Activity ◽  
Peripheral Tissues ◽  
Brown Adipose ◽  
The Central Nervous System

Abstract The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function.

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