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A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin.

ABSTRACT: Leptin regulates energy expenditure and body weight by acting both on the hypothalamus and on peripheral targets. Central actions of leptin are enhanced by cholecystokinin (CCK). The interaction between leptin and CCK makes physiological sense, as rats lacking CCK1 receptors are resistant to peripheral leptin but not to leptin directly infused into the brain. We have recently reported that CCK enhances leptin effects by increasing the entry of leptin into the CNS. The aim of this work was to further characterize the effect of CCK (10 microg kg(-1)) on leptin kinetics as well as the CCK receptor subtype involved in the interaction between CCK and leptin.Experiments were carried out both in free-feeding and in fasted rats receiving a single dose of leptin (100 microg kg(-1); i.p.). Parameters analysed over the next 6 h were plasma and cerebrospinal fluid concentrations of leptin.We observed that CCK-8 depressed the increase in plasma leptin that followed the i.p. injection and simultaneously increased leptin concentration in the cerebrospinal fluid from 92+/-25 to 230+/-24 pg mL(-1) (P<0.05). The effect of CCK-8 was totally prevented by the CCK1 receptor antagonist, SR-27,897 (0.3 mg kg(-1), s.c.), but not by the CCK2 receptor antagonist, L-365,260 (1 mg kg(-1)).These results show that CCK plays a role in regulating the access of leptin to the brain and suggest that CCK analogues, acting on CCK1 receptors, might be useful drugs in improving leptin actions within the brain.

SUBMITTER: Cano V

PROVIDER: S-EPMC2451056 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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A Novel CCK Receptor GPR173 Mediates Potentiation of GABAergic Inhibition.

Project description:Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.

| S-EPMC10072296 | biostudies-literature

Immunoglobulin-like domain receptor 1 mediates fat-stimulated cholecystokinin secretion.

Project description:Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild type but not ILDR1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation is associated with increased [Ca2+]i consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion. GFP positive cells from CCK-EGFP transgenic mice were isolated by FACS and the expression profile was compared with an equal number of non-fluorescent intestinal cells.

2013-05-23 | E-GEOD-47196 | biostudies-arrayexpress

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging.

Project description:Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.

| S-EPMC7773352 | biostudies-literature

Immunoglobulin-like domain receptor 1 mediates fat-stimulated cholecystokinin secretion.

2013-05-23 | GSE47196 | GEO

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion.

Project description:Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca2+]i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.

| S-EPMC3726170 | biostudies-literature

Novel function of cholecystokinin (CCK): Mediator between feeding and gonadal development

Project description:We used single cell RNA sequencing (scRNA-seq)to analyze the pituitary cells in Ctenopharyngodon idellus

2025-01-29 | GSE269034 | GEO

Novel function of cholecystokinin (CCK): Mediator between feeding and gonadal development

Project description:We used single cell RNA sequencing (scRNA-seq)to analyze the hypothalamu cells in Ctenopharyngodon idellus

2025-01-29 | GSE268914 | GEO

Permeability of dopamine D2 receptor agonist hordenine across the intestinal and blood-brain barrier in vitro

Project description:Hordenine, a bioactive food compound, has several pharmacological properties and has recently been identified as a dopamine D2 receptor (D2R) agonist. Since the pharmacokinetic profile of hordenine has been described to a limited extent, the present study focused on the transfer and transport of hordenine across the intestinal epithelium and the blood-brain barrier (BBB) in vitro. Hordenine was quickly transferred through the Caco-2 monolayer in only a few hours, indicating a rapid oral uptake. However, the high bioavailability may be reduced by the observed efflux transport of hordenine from the bloodstream back into the intestinal lumen and by first pass metabolism in intestinal epithelial cells. To determine the biotransformation rate of hordenine, the metabolite hordenine sulfate was synthesized as reference standard for analytical purposes. In addition, transfer studies using primary porcine brain capillary endothelial cells (PBCEC) showed that hordenine is able to rapidly penetrate the BBB and potentially accumulate in the brain. Thus, a D2R interaction of hordenine and activation of dopaminergic signaling is conceivable, assuming that the intestinal barrier can be circumvented by a route of administration alternative to oral uptake.

| S-EPMC9202863 | biostudies-literature

Increased Leptin and Leptin Receptor Expression in Dogs With Gallbladder Mucocele.

Project description:BackgroundLeptin and its receptor play a role in several disease processes such as pancreatitis and heart disease. However, their association with gallbladder mucocele (GBM) in dogs has not been reported.Hypothesis/objectivesTo evaluate differences in the expression of leptin and leptin receptor between dogs with and without GBM.AnimalsTwenty-five healthy dogs, including 9 laboratory beagle dogs, and 22 client-owned dogs with GBM.MethodsSerum leptin concentration was determined in blood samples of all dogs by ELISA. Canine gallbladder samples were collected from 9 dogs with GBM that underwent surgery for therapeutic purposes and from 9 healthy laboratory beagle dogs as a normal control group. Samples were analyzed for leptin and leptin receptor mRNA by real-time polymerase chain reaction.ResultsSerum leptin concentration was significantly higher in dogs with GBM than in healthy dogs (medians of 7.03 and 2.18 ng/mL, respectively; P < .001). Patients with GBM that had undergone surgery had significantly higher serum leptin concentrations than those that had not (medians of 12.2 and 4.09 ng/mL, respectively; P = .001). However, no difference in serum leptin concentration was found between dogs with GBM with or without endocrinopathies. The mRNA expression levels of leptin and its receptor were significantly increased in the gallbladder tissues of dogs with GBM.Conclusions and clinical importanceDysregulation of leptin might be involved in the pathophysiology of GBM, and leptin concentrations might be associated with GBM severity.

| S-EPMC5259632 | biostudies-literature

Leptin receptor mRNA in rat brain astrocytes.

Project description:We recently reported that mouse astrocytes express leptin receptors (ObR), and that obesity induces upregulation of astrocytic ObR. To provide further evidence of the importance of astrocytic ObR expression, we performed double-labeling fluorescent in situ hybridization (FISH) and immunohistochemistry in the rat hypothalamus. Laser confocal microscopic image analysis showed that ObR mRNA was present in glial fibrillary acidic protein (+) cells that show distinctive astrocytic morphology as well as in neurons. In addition to the presence of ObR mRNA, ObR protein was shown in both astrocytes and neurons in the rat hypothalamus by double-labeling immunohistochemistry. In cultured rat C6 astrocytoma cells treated with different doses of lipopolysaccharide for 6h, the mRNA for ObRa or ObRb did not show significant changes, as measured by quantitative RT-PCR. However, the protein expression of both ObRa and ObRb, determined by Western blotting, was increased after the C6 cells were treated with either lipopolysaccharide or tumor necrosis factor-alpha. The results indicate that astrocytic ObR expression is present in rats as well as mice, and that it probably plays a role in the neuroinflammatory response.

| S-EPMC2787995 | biostudies-literature

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