Gut-brain Hormone Research Articles

Modulation of Microbiota-Gut-Brain Axis by Berberine Resulting in Improved Metabolic Status in High-Fat Diet-Fed Rats

Objective: To investigate whether or not berberine could improve metabolic status of high-fat-fed rats through modulation of microbiota-gut-brain axis. Methods: Berberine was administered on high-fat-fed Sprague-Dawley rats. Brain-gut hormones were detected, and changes of gut microbiota were analyzed by 16S rRNA gene sequencing. Results: Berberine could reduce weight gain and lipolysis in the high-fat diet-fed group. Moreover, trends of ameliorated insulin resistance and decreased endogenous glucose production were observed. In addition, the microbiota-gut-brain axis was found to be modulated, including structural and diversity changes of microbiota, elevated serum glucagon-like peptide-1 and neuropeptide Y level, decreased orexin A level, up-regulated glucagon-like peptide-1 receptor mRNA level as well as ultra-structural improvement of the hypothalamus. Conclusion: Taken together, our findings suggest that berberine improved metabolic disorders induced by high-fat diet through modulation of the microbiota-gut-brain axis.

A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice

Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg6Phe7 in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg6 in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

Changes in levels of selected incretins and appetite-controlling hormones following surgical treatment for morbid obesity.

IntroductionThe hormonal brain-gut axis is a crucial element in appetite control and the response to surgical treatment for super obesity. However, mechanisms underlying the metabolic response to surgical treatment for morbid obesity are still not clearly specified.AimTo evaluate and compare the effects of surgical treatment for super obesity by laparoscopic sleeve gastrectomy (LSG) and by laparoscopic Roux-en-Y gastric bypass (LRYGB) on selected incretins and appetite-controlling hormones.Material and methodsThirty-five patients were enrolled in a prospective study. Laparoscopic sleeve gastrectomy was performed in 45.8% of patients, and LRYGB in the remaining 54.2% of patients. Before the procedure fasting blood serum was collected from patients and preserved, to determine levels of selected incretins and brain-gut hormones: glucagon-like peptide 1 (GLP-1), peptide YY (PYY), leptin, and ghrelin.ResultsTwenty-eight patients came to a follow-up visit 12 months after the surgery. In these patients selected parameters were determined again. The percentage weight loss was 58.8%. The ghrelin levels had decreased, and no statistically significant difference was observed between the two procedures. After both surgical procedures a statistically significant reduction in the leptin level was also observed. Peptide YY levels statistically significantly increased in the whole studied group. The GLP-1 level increased after the surgical procedure. However, the observed change was not statistically significant.ConclusionsBoth treatment methods result in modification of secretion patterns for selected gastrointestinal hormones, and this was considered to be a beneficial effect of bariatric treatment. The laparoscopic sleeve gastrectomy, being a procedure resulting in a metabolic response, seems to be an equally effective method for treatment of super obesity and comorbidities as the laparoscopic gastric bypass.

Sub-chronic Ghrelin Receptor Blockade Attenuates Alcohol- and Amphetamine-Induced Locomotor Stimulation in Mice.

Ghrelin initially emerged as a gut-brain hormone controlling food intake, meal initiation and appetite mainly via hypothalamic circuits in both rodents and humans. The findings that ghrelin receptors (GHS-R1A) are expressed in reward-related areas, including the nucleus accumbens (NAc) and ventral tegmental area (VTA), suggest that ghrelin is a novel reward regulator. Indeed, ghrelin signalling mediates the rewarding and motivational properties of addictive drugs. In addition, daily co-administration of a GHS-R1A antagonist and various addictive drugs prevents the drug-induced locomotor sensitization in rats. The present series of experiment were designed to evaluate the effect of repeated pharmacological GHS-R1A suppression on drug-induced locomotor stimulation in more detail. We showed that sub-chronic pre-treatment of the GHS-R1A antagonist, JMV2959, attenuated the ability of acute administration of alcohol as well as of amphetamine to stimulate locomotion. However, there was no effect of sub-chronic JMV2959 treatment on locomotor activity per se or on the expression of the GHS-R1A gene (Ghsr) in the VTA or the NAc compared with vehicle treatment. In addition, sub-chronic ghrelin treatment caused a locomotor sensitization. While previous research has pinpointed ghrelin as an appetite regulator the present study together with previous studies suggest that ghrelin signalling modulates various reward-mediated behaviours in rodents. Collectively, this suggests that the GHS-R1A could be a key target for novel treatment strategies for addiction.

Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy.

Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic “ghrelin receptors” (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic–dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence.

Role of Ghrelin in Drug Abuse and Reward-Relevant Behaviors: A Burgeoning Field and Gaps in the Literature

Ghrelin is a gut-brain hormone that regulates energy balance through food consumption. While ghrelin is well known for its role in hypothalamic activation and homeostatic feeding, more recent evidence suggests that ghrelin also is involved in hedonic feeding through the dopaminergic reward pathway. This paper investigated how ghrelin administration (intraperitoneal, intracerebroventricular, or directly into dopaminergic reward-relevant brain regions) activates the dopaminergic reward pathway and associated reward-relevant behavioral responses in rodents. A total of 19 empirical publications that examined one or more of these variables were included in this review. Overall, ghrelin administration increases dopamine levels in the nucleus accumbens, as well as reward-relevant behaviors such as food (both standard chow and palatable foods) and alcohol consumption. Ghrelin administration also increases operant responding for sucrose, and conditioned place preference. Following a review of the small body of literature examining the effects of ghrelin administration on the dopamine reward pathway, we present a model of the relationship between ghrelin and dopaminergic reward activation. Specifically, ghrelin acts on ghrelin receptors (GHS-R1A) in the ventral tegmental area (VTA) and lateral dorsal tegmental nucleus (LDTg) to stimulate the mesolimbic dopamine reward pathway, which results in increased rewarding behaviors in rodents. Results from this review suggest that selective antagonism of the ghrelin system may serve as potential treatment for addictive drug use. This review highlights gaps in the literature, including a lack of examination of sex- or age-related differences in the effects of ghrelin on dopamine reward processes. In light of vulnerability to drug abuse among female and adolescent populations, future studies should target these individual difference factors.

Ghrelin administration enhances neurogenesis but impairs spatial learning and memory in adult mice

Ghrelin, an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents, was reported to enhance both adult neurogenesis and hippocampus-dependent memory formation. However, it is still unclear whether ghrelin-induced hippocampus neurogenesis is responsible for its memory improvement. Using 5-bromo-2′ deoxyuridien (BrdU) to birth-date newborn neurons and c-Fos expression to identify dentate gyrus (DG) neurons involved in memory processes, we checked here the effect of ghrelin treatment on adult neurogenesis and cognitive behaviors in mice. We further examined the possible effect of ghrelin on the recruitment of new neurons into the spatial memory traces in intact mice. We found that systemic ghrelin treatment (80μg/kg, ip injection once daily for 8days) stimulated neurogenesis in the adult hippocampus, but had no effect on spatial memory formation. Consistently, it did not affect the incorporation of newborn neurons into the spatial memory circuits. On the contrary, local infusion of ghrelin (8ng/0.5μl into CA1 region of the hippocampus) impaired spatial memory formation, but did not affect adult neurogenesis. Our results thus suggested that ghrelin plays distinct roles in modulating adult neurogenesis and the memory acquisition in the hippocampus, the two processes may not be correlated and may be mediated by different mechanisms.

Ghrelin receptor (GHS-R1A) antagonism suppresses both alcohol consumption and the alcohol deprivation effect in rats following long-term voluntary alcohol consumption.

Alcohol dependence is a heterogeneous disorder where several signalling systems play important roles. Recent studies implicate that the gut-brain hormone ghrelin, an orexigenic peptide, is a potential mediator of alcohol related behaviours. Ghrelin increases whereas a ghrelin receptor (GHS-R1A) antagonist decreases alcohol consumption as well as operant self-administration of alcohol in rodents that have consumed alcohol for twelve weeks. In the present study we aimed at investigating the effect of acute and repeated treatment with the GHS-R1A antagonist JMV2959 on alcohol intake in a group of rats following voluntarily alcohol consumption for two, five and eight months. After approximately ten months of voluntary alcohol consumption the expression of the GHS-R1A gene (Ghsr) as well as the degree of methylation of a CpG island found in Ghsr was examined in reward related brain areas. In a separate group of rats, we examined the effect of the JMV2959 on alcohol relapse using the alcohol deprivation paradigm. Acute JMV2959 treatment was found to decrease alcohol intake and the effect was more pronounced after five, compared to two months of alcohol exposure. In addition, repeated JMV2959 treatment decreased alcohol intake without inducing tolerance or rebound increase in alcohol intake after the treatment. The GHS-R1A antagonist prevented the alcohol deprivation effect in rats. There was a significant down-regulation of the Ghsr expression in the ventral tegmental area (VTA) in high- compared to low-alcohol consuming rats after approximately ten months of voluntary alcohol consumption. Further analysis revealed a negative correlation between Ghsr expression in the VTA and alcohol intake. No differences in methylation degree were found between high- compared to low-alcohol consuming rats. These findings support previous studies showing that the ghrelin signalling system may constitute a potential target for development of novel treatment strategies for alcohol dependence.

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

Ghrelin Modulates Lateral Amygdala Neuronal Firing and Blocks Acquisition for Conditioned Taste Aversion

Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. An increasing number of studies have reported that ghrelin and its identified receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), produces remarkably wide and complex functions and biological effects on specific populations of neurons in central nervous system. In this study, we sought to explore the in vivo effects of acute ghrelin exposure on lateral amygdala (LA) neurons at the physiological and behavioral levels. In vivo extracellular single-unit recordings showed that ghrelin with the concentration of several nanomolars (nM) stimulated spontaneous firing of the LA neurons, an effect that was dose-dependent and could be blocked by co-application of a GHS-R1a antagonist D-Lys3-GHRP-6. We also found that D-Lys3-GHRP-6 inhibited spontaneous firing of the LA neurons in a dose-dependent manner, revealing that tonic GHS-R1a activity contributes to orchestrate the basal activity of the LA neurons. Behaviorally, we found that microinfusion of ghrelin (12 ng) into LA before training interfered with the acquisition of conditioned taste aversion (CTA) as tested at 24 h after conditioning. Pre-treatment with either purified IgG against GHS-R1a or GHS-R1a antagonist blocked ghrelin’s effect on CTA memory acquisition. Ghrelin (12 ng) had no effect on CTA memory consolidation or the expression of acquired CTA memory; neither did it affect the total liquid consumption of tested rats. Altogether, our data indicated that ghrelin locally infused into LA blocks acquisition of CTA and its modulation effects on neuronal firing may be involved in this process.

Correlations of macronutrient-induced functional magnetic resonance imaging signal changes in human brain and gut hormone responses

Body energy homeostasis is largely regulated by the interactions between appetite-related brain regions and gut hormones. We hypothesized that the sensitivity of appetite-related brain regions [eg, hypothalamus, insula, thalamus, parahippocampal/hippocampal cortex, caudate, putamen, amygdala, and orbitofrontal cortex (OFC)] varies for each macronutrient, and the differential sensitivity is associated with gut hormone concentrations in humans. Brain activation responses to ingested fat, glucose, protein, and water in the above-mentioned 8 brain regions of 14 healthy men were investigated by using functional magnetic resonance imaging. Fasting and postprandial plasma glucose, insulin, ghrelin, cholecystokinin (CCK), and glucagon-like peptide 1 (GLP-1) concentrations were measured. The relation of the blood oxygen level-dependent (BOLD) signal with plasma glucose and hormone concentrations was assessed by using Pearson's correlation analysis. Ingested macronutrients similarly reduced the BOLD signal in the middle insula, thalamus, parahippocampal cortex, caudate, and lateral OFC. Protein ingestion reduced the BOLD signal in the amygdala more effectively than did fat and glucose ingestion. BOLD signal changes were positively correlated with circulating ghrelin concentrations and were negatively correlated with circulating insulin, CCK, and GLP-1 concentrations. The findings indicate variations in the correlation between brain activation and plasma hormone concentrations after ingestion of different macronutrients. The middle insula, thalamus, parahippocampal cortex, caudate, and lateral OFC, but not the amygdala, have similar sensitivities to isocaloric and isovolumetric macronutrient solutions. Differential correlations exist between BOLD signal changes in activated brain regions and postprandial changes in plasma concentrations of different gut hormones in response to the ingestion of different macronutrients. This trial was registered at chictr.org as ChiCTR-TRC-12001945.

Brain GLP-1 Signaling Regulates Femoral Artery Blood Flow and Insulin Sensitivity Through Hypothalamic PKC-δ

OBJECTIVEGlucagon-like peptide 1 (GLP-1) is a gut-brain hormone that regulates food intake, energy metabolism, and cardiovascular functions. In the brain, through a currently unknown molecular mechanism, it simultaneously reduces femoral artery blood flow and muscle glucose uptake. By analogy to pancreatic β-cells where GLP-1 activates protein kinase C (PKC) to stimulate insulin secretion, we postulated that PKC enzymes would be molecular targets of brain GLP-1 signaling that regulate metabolic and vascular function.RESEARCH DESIGN AND METHODSWe used both genetic and pharmacological approaches to investigate the role of PKC isoforms in brain GLP-1 signaling in the conscious, free-moving mouse simultaneous with metabolic and vascular measurements.RESULTSIn normal wild-type (WT) mouse brain, the GLP-1 receptor (GLP-1R) agonist exendin-4 selectively promotes translocation of PKC-δ (but not -βII, -α, or -ε) to the plasma membrane. This translocation is blocked in Glp1r−/− mice and in WT mice infused in the brain with exendin-9, an antagonist of the GLP-1R. This mechanism coordinates both blood flow in the femoral artery and whole-body insulin sensitivity. Consequently, in hyperglycemic, high-fat diet–fed diabetic mice, hypothalamic PKC-δ activity was increased and its pharmacological inhibition improved both insulin-sensitive metabolic and vascular phenotypes.CONCLUSIONSOur studies show that brain GLP-1 signaling activates hypothalamic glucose-dependent PKC-δ to regulate femoral artery blood flow and insulin sensitivity. This mechanism is attenuated during the development of experimental hyperglycemia and may contribute to the pathophysiology of type 2 diabetes.

The role of the brain in the regulation of metabolism and energy expenditure: the central role of insulin, the insulin resistance of the brain

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Molecular characterization, appetite regulatory effects and feeding related changes of peptide YY in goldfish

Peptide YY (PYY) is a 36 amino acid multifunctional gut–brain hormone in mammals. PYY has recently raised great interest as it was shown to reduce food intake and body weight of mammals. While PYY and its receptors have been sequenced from many non-mammalian vertebrates, its functional role, especially in the regulation of food intake in lower vertebrates remain unknown. In this study, we identified the gene organization of goldfish PYY (gfPYY) and found abundant expression of PYY mRNA in the brain and digestive tract of goldfish. A 2.5-fold increase at 3 h post-feeding and a 1.5-fold decrease in fasted animals was observed of PYY mRNA expression in the brain, suggesting an anorectic role for PYY in goldfish. A single intraperitoneal injection of 10 ng/g body weight gfPYY(1–36) or an intracerebroventricular injection of 5 ng/g body weight gfPYY(1–36) caused a 27% or 30% reduction in food intake in goldfish, respectively. Overall, our results, for the first time provide molecular and functional evidence for anorectic actions of PYY in goldfish.

Pancreatic α-cell dysfunction in diabetes

A major, yet poorly understood, feature of type 2 diabetes is the excessive hepatic glucose production and the corresponding insulin resistance leading to fasting hyperglycaemia. The tremendous amount of work done to provide the physiological and molecular mechanisms explaining this impairment has led to the emergence of several consensual hypotheses. Among these, is the increased daily and unregulated plasma glucagon concentration in type 2 diabetic patients. Therefore, studies aiming to understand the physiological regulation of glucagon secretion and the corresponding impairment during diabetes are directly relevant to the treatment of type 2 diabetes. Glucagon secretion by α-cells is an immediate response to glucopenia. Abnormal secretion of glucagon and other counterregulatory hormones is a hallmark of type 1 and type 2 diabetes and a major limitation to the use of strong hypoglycaemia agents. A few molecular mechanisms of glucose detection triggering counterregulation and in particular inducing glucagon secretion or suppressing it during hyperglycaemic episodes, have been identified. Such mechanisms are related to those of the insulin secreted β-cell. The glucose transporter GLUT2 and the K-ATP dependent channel, as well as regulatory mechanisms, involved the central nervous system and the gut-brain hormone GLP-1. Over the last years, glucoincretins have provided promising results for the normalization of plasma glucagon concentration of type 2 diabetic patients, which could partly explain the therapeutic benefits of incretin-related therapy. The underlined mechanisms of GLP-1 regulated glucagon secretion are most likely related to the action of the hormone on the activation of the portal and brain glucose sensors. Certainly, strategies aiming to restore glucose-regulated glucagon secretion are important milestones for the treatment of diabetic patient and the prevention of iatrogenic hypoglycaemia.

Visualization of ghrelin-producing neurons in the hypothalamic arcuate nucleus using ghrelin-EGFP transgenic mice

The gut–brain hormone ghrelin is known to stimulate growth hormone release from the pituitary gland, and to regulate appetite and energy metabolism. Ghrelin-containing neurons have been shown to form neuronal network with several types of appetite-regulating neurons in the hypothalamus. Although ghrelin-containing cell bodies have been reported to localize in the hypothalamic arcuate nucleus, the published results present large discrepancies regarding the localization of ghrelin-positive cell bodies in the brain. In order to address this issue, we have generated a transgenic mouse model by microinjecting a DNA construct in which the transcription regulatory regions of ghrelin drive the enhanced green fluorescent protein (EGFP) gene. These transgenic mice expressed EGFP and ghrelin mRNA in the stomach and hypothalamus. Double immunostaining revealed that GFP-like immunoreactivity was co-localized with ghrelin-like immunoreactivity in the stomach of these animals, while EGFP fluorescence was clearly demonstrated in the hypothalamic arcuate nucleus by confocal laser microscopy. The ghrelin-EGFP transgenic mouse model described in this study therefore provides a powerful tool with which to analyze ghrelin neuronal circuits in the brain and should contribute to our understanding of the functional significance of ghrelin in the central nervous system.

Ghrelin is Present in Teeth

Ghrelin belongs to the family of a gut-brain hormone that promotes food intake and controls energy balance. Recently, it has also been shown to regulate bone formation directly. Dental tissue shares several functional, developmental and anatomical similarities with bone, and in the present study we have investigated the presence of ghrelin in 44 human teeth using immunocytochemistry and radioimmunoassay. Both methods showed that the hormone is present in canines and molars, mainly in the odontoblasts but also in the pulp. Ghrelin could potentially play interesting physiological roles in teeth.

Interoceptive “satiety” signals produced by leptin and CCK

The present studies assessed the extent to which the adiposity signal leptin and the brain–gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1 h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 μg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 μg, i3vt) combined with CCK-8 (2 μg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5 mg/kg). Although neither dose suppressed intake, the 0.3 mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to “satiety”.

Association Between Ghrelin Gene Variations and Blood Pressure in Subjects With Impaired Glucose Tolerance

Ghrelin is a gut-brain hormone, which stimulates food intake and controls energy balance. Recently, it has been shown that ghrelin may also play a role in the regulation of blood pressure (BP) by acting at the sympathetic nervous system. In the present study we genotyped six variants of the ghrelin gene and its promoter, and tested whether these single nucleotide polymorphisms (SNPs) were associated with BP levels in participants of the Finnish Diabetes Prevention Study. The Finnish Diabetes Prevention Study was a longitudinal study where 522 subjects with impaired glucose tolerance were randomized into either an intervention or control group. DNA was available from 507 subjects (mean body mass index [BMI] 31.2+/-4.5 kg/m2, age 55+/-7 years). All six SNPs were screened by the restriction fragment length polymorphism method. Subjects with the most common genotype combination of the following four SNPs, -604G/A, -501A/C, Leu72Met, and Gln90Leu, had the lowest systolic (131+/-11 v 137+/-13 mm Hg, P=.003) and diastolic BP levels (79+/-7 v 83+/-7 mm Hg, P=.004) at the baseline of the study and during 3 years of follow-up compared to all other genotypes. Adjustments for age, gender, antihypertensive medication, BMI, waist circumference, and alcohol intake did not change this association. Several ghrelin gene variations were associated with BP levels in subjects with impaired glucose tolerance.

Targeting Cytotoxic Conjugates of Somatostatin, Luteinizing Hormone- Releasing Hormone and Bombesin to Cancers Expressing Their Receptors: A “Smarter” Chemotherapy

Chemotherapy is one of the main modalities in the therapy of cancer. However, an improvement in the efficacy and a reduction in the toxicity of chemotherapeutic agents remains a great challenge to oncologists. A specific delivery of cytotoxic drugs to cancerous cells may help improving both aspects. Peptide hormones, for which receptors have been found in various human cancers, can serve as carriers for a local delivery of cytotoxic agents or radiopharmaceuticals to the tumors, as demonstrated by the successful clinical use of radiolabeled somatostatin analog Octreoscan for the detection and treatment of some somatostatin receptor-positive tumors. Thus, in recent years we developed a series of cytotoxic peptide hormone conjugates based on derivatives of hypothalamic hormones such as somatostatin and luteinizing hormone-releasing hormone (LHRH), and the brain-gut hormone bombesin. To create targeted conjugates with high cytotoxic activity, a derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), which is 500-1, 000 times more active than its parent compound, was developed. This agent was coupled to somatostatin octapeptide RC-121 to form cytotoxic conjugate AN-238, and to [D-Lys6]LHRH carrier to produce analog AN-207. Cytotoxic bombesin hybrid AN-215 also contains AN-201. DOX was likewise linked to [D-Lys6]LHRH to form AN-152. A comprehensive testing of these cytotoxic conjugates in experimental models of various human and rodent cancers led to their selection as candidates for clinical trials.