Orexigenic Peptide Research Articles

Weight-Reducing Dietary Intervention Increases the Ability of Hyperinsulinemia to Suppress Serum Ghrelin Concentration in Individuals with Obesity

BackgroundGhrelin is an orexigenic peptide secreted mainly by the stomach. Serum ghrelin concentrations are suppressed after a meal, probably due to insulin release. Individuals with obesity are characterized by a lower fasting serum ghrelin and a lower ghrelin decrease after a meal. The effect of weight loss on the ability of insulin to suppress serum ghrelin concentration remains unknown. ObjectiveThe aim of the present study was to analyze the effect of weight-reducing dietary intervention on the ability of hyperinsulinemia to suppress serum ghrelin concentration in young individuals with uncomplicated obesity. MethodsWe examined 38 individuals with marked overweight or obesity, who underwent a 12-wk dietary intervention program. Serum ghrelin concentration was measured before and after a 2-h hyperinsulinemic–euglycemic clamp, both pre- and post-intervention. Twenty normal-weight individuals served as a control group and were examined at baseline only. ResultsIndividuals with overweight/obesity were characterized by a lower fasting serum ghrelin concentration than normal-weight individuals (P = 0.006). Insulin decreased serum ghrelin concentration in both groups (P < 0.001); however, this decrease was markedly lower in individuals with overweight/obesity than in normal-weight individuals (99.70 ± 136.37 vs. 215.45 ± 250.28 pg/mL; P = 0.026). Fasting serum ghrelin concentration increased after the intervention. After weight-reducing dietary intervention, the decrease in serum ghrelin concentration after the clamp was significantly greater than the pre-intervention value (99.70 ± 136.37 vs. 221.82 ± 228.75 pg/mL; P = 0.002). ConclusionsWeight-reducing dietary intervention restores the ability of hyperinsulinemia to suppress serum ghrelin concentration. It may suggest an enhanced feeling of satiety after moderate weight loss in individuals with overweight/obesity.

Ghrelin receptor antagonism and satiety attenuate Pavlovian-instrumental transfer

Animals rely on learned cues to guide their behaviour for rewards such as food. The Pavlovian-instrumental transfer (PIT) task can be used to investigate the influence of Pavlovian stimuli on instrumental responding. Ghrelin, an orexigenic peptide, and its receptor, growth hormone secretagogue receptor 1A (GHS-R1A), has received growing interest for its role in reward-motivated learning and behaviours. A significant population of GHS-R1A have been identified within the ventral tegmental area (VTA), a critical node in the mesolimbic reward circuit that is necessary for the expression of PIT. As ghrelin has been found to increase dopaminergic activity in the VTA, we predicted that GHS-R1A antagonism with JMV-2959 would attenuate PIT. Further, given the relationship between hunger levels and changes in ghrelin signalling, we sought to compare the effects GHS-R1A antagonism with those of satiety, hypothesizing parallel effects, with each attenuating PIT. Rats received daily sessions of Pavlovian and then instrumental training over 3 weeks. Across three experiments, we examined the effects of a shift to satiety, or treatment with the GHS-R1A antagonist JMV-2959, either peripherally or directly into the VTA. We found that presentations of a stimulus paired with food reward enhanced responding for food across all conditions, thus demonstrating the expected PIT effect. Further, GHS-R1A antagonism, both peripherally and within the VTA, as well as satiety significantly reduced the magnitude of the PIT effect compared to control conditions. These results clarify our understanding of ghrelin signalling in PIT and begin to elucidate the role of feeding-related peptides in the modulation of reward-related responding.

High-Fat Diet Induces Resistance to Ghrelin and LEAP2 Peptide Analogs in Mice.

Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.

24 Effects of Gestational and Postweaning Nutrition on Brain Development and Puberty in Beef Heifers

Abstract Approximately 5 million beef heifers enter the U.S. cow herd annually, and their lifetime productivity is largely dependent upon their ability to attain puberty and produce a calf by 24 mo of age. However, a considerable proportion of heifers within existing U.S. production systems fail to achieve these goals, particularly in southern regions where Bos indicus-influenced cattle predominate. Consequently, managerial approaches are needed that employ nutritional programming of the reproductive neuroendocrine axis, while minimizing feeding costs and optimizing the consistent attainment of puberty by approximately 14 mo of age. Our previous research has clearly demonstrated that increased BW gain between 4 and 8 mo of age facilitates pubertal development by programming hypothalamic centers that regulate gonadotropin releasing-hormone (GnRH) secretion. Among the different metabolic hormones, leptin has a critical role in conveying nutritional information to the hypothalamus and controlling puberty. Two hypothalamic neuronal populations that express the orexigenic peptide neuropeptide Y (NPY) and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH; a product of the POMC gene) are key components of afferent pathways that convey inhibitory (NPY) and excitatory (αMSH) inputs to GnRH and kisspeptin neurons. Our studies have demonstrated that short-term increases in dietary energy intake after early weaning at 4 mo of age result in epigenetic, structural, and functional modifications in these hypothalamic pathways to promote high-frequency, episodic release of GnRH and luteinizing hormone. However, integrating the foundational knowledge of metabolic imprinting of the brain for early puberty with issues related to lifetime performance is complex. One approach has been to employ a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding during juvenile development. This approach is designed to support early onset of puberty by imprinting functional alterations in the hypothalamus during key periods of brain development while optimizing other aspects of growth and performance. Finally, while several key processes of fetal brain development occur during late gestation, neither maternal undernutrition (BCS 3.0-3.5) nor maternal obesity (BCS 7.5-8.0) during the last two trimesters of gestation impacted the organization of hypothalamic neurocircuitries controlling GnRH/LH secretion or age at puberty in the heifer offspring. Collectively, these results indicate that the adult reproductive phenotype in Bos indicus-influenced females is resilient to significant degrees of nutritional stress imposed during prenatal development, particularly if early gestation (first trimester) is avoided. These findings are in contrast with reports in Bos taurus females in which late gestation nutritional extremes result in delayed puberty in heifer offspring, suggesting that potential genotype-specific differences may exist. Research support: USDA-NIFA-AFRI (2018-67015-27595 and 2021-67015-33676).

The Acute Effect of Hydroxychloroquine Sulfate on Hunger, the Plasma Concentration of Orexigenic Peptides and Hedonic Food Intake: A Pilot Study.

The direct infusion of bitter solutions in the gastrointestinal tract can reduce the secretion of orexigenic hormones and influence appetite and food intake. We aimed to explore whether oral ingestion of the bitter tastant hydroxychloroquine sulfate can exert similar effects. Ten lean adult women were included in this double-blind, randomized, two-visit, crossover study. After an overnight fast, each volunteer received film-coated tablets containing 400 mg of hydroxychloroquine sulfate (Plaquenil®) or placebo. Plasma-ghrelin, -motilin, -insulin and blood-glucose concentrations were determined every 10 min before and 30 min after feeding; appetite was scored every 10 min. Hunger scores were investigated with a special interest 50-60 min after the ingestion of hydroxychloroquine sulfate, right before a rewarding chocolate milkshake was offered to drink ad libitum. Compared with the placebo, hydroxychloroquine sulfate tended to reduce hunger at the time of interest (p = 0.10). No effect was found upon subsequent milkshake intake. Motilin plasma concentrations were unaltered, but acyl-ghrelin plasma concentrations decreased after the ingestion of hydroxychloroquine sulfate (t = 40-50; p < 0.05). These data suggest that the oral intake of hydroxychloroquine sulfate tablets reduces subjective hunger via a ghrelin-dependent mechanism but does not affect motilin release, hedonic food intake or insulin levels in healthy women.

Brain-derived neurotrophic factor (BDNF) activates PI3K-AKT-mTOR signaling via hypothalamic TrkB receptors to reduce feeding in Siberian sturgeon (Acipenser baerii)

Although Brain-derived neurotrophic factor (BDNF) has been identified as an orexigenic peptide in zebrafish, its role in regulating feeding behavior in other fish species is still unclear. This study aimed to investigate the regulatory role of BDNF in feeding behavior of Siberian sturgeon (Acipenser baerii). The bdnf and its receptor TrkB genes (Abbdnf and AbTrkB) of Siberian sturgeon were cloned and found to be most highly expressed in the hypothalamus. Short- and long-term fasting experiments showed that Abbdnf and AbTrkB mRNA levels decreased in the hypothalamus after fasting, but increased after refeeding, consistent with the pattern observed for anorexigenic peptides. The NGF(nerve growth factor) structural domain has an important role in mediating the binding of BDNF to the TrkB receptor. To explore the feeding regulatory role of BDNF, recombinant AbBDNFNGF protein was expressed using prokaryotic expression system. Intraperitoneal injection of AbBDNFNGF suppressed cumulative food intake at 1 h, 3 h, and 6 h after administration, and resulted in upregulation of anorexigenic peptides (pomc and leptin) mRNA and downregulation of orexigenic peptides (npy and agrp) mRNA in both central and peripheral tissues. Additionally, AbBDNFNGF injection led to activation of TrkB receptors and pi3k-akt-mtor signaling pathway in the hypothalamus. Overall, this study confirms the anorexigenic effect of BDNF in Siberian sturgeon.

Acylated- and unacylated ghrelin during an oral glucose tolerance test in humans at risk for type 2 diabetes mellitus

Background/ObjectivesThe orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity.Subjects/MethodsIn this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²–76.25 kg/m²).ResultsFasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90–120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m².ConclusionOur data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.

Morphological study of neuropeptide Y expression in human and mouse anterior insular cortex: Overexpression in the insular cortex and nucleus accumbens in obese mice on a long-term obesogenic diet

BackgroundThe anterior lobe of the insular cortex (aINS) is a cortical region that has reciprocal connections with limbic centers such as the anterior cingulate cortex, prefrontal cortex, amygdala and nucleus accumbens (NAc). In fact, the aINS has been involved in the integration of autonomic information for emotional and motivational functions. The compulsive consumption of drugs or high-fat foods induces alterations at both behavioural and brain levels. Brain reward circuits are altered in response to continued intake, in particular the dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The aINS has multiple connections with the components of this system. In recent years, efforts have been made to better understand the fundamental role of the aINS in addiction, making it one of the key centres of interest for research into new treatments for addiction. ObjectivesThe present work focuses on studying 1.- whether the human aINS expresses orexigenic peptides such as neuropeptide Y (NPY), a peptide known to induce hyperphagia, and which has been implicated in the onset and development of obesity, 2.- the long-term effect of an obesogenic diet on NPY expression in the aINS and NAc of C57BL/6 mice. MethodsA total of 17 female C57BL/6 J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were seven female mice on the SD and ten on the HFD. The duration of the experiment was 180 days. We also studied 3 human adult brains (1 male and 2 females, mean age 55.7 ± 5.2 years). The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of NPY neurons of the aINS and NAc of humans and mice. ResultsOur morphological analysis demonstrates for the first time the basal expression of NPY in different layers of the human cortex (II, III, IV, V/VI), in a pattern similar to previous studies in other species. Furthermore, we observed an increase in the number of NPY-positive cells and their intracytoplasmic signal in the aINS and NAc of the obese mice subjected to a long-term obesogenic diet. ConclusionsTo our knowledge, this is the first study to show the distribution and expression of NPY in the human INS and how its expression is altered after prolonged treatment with an obesogenic diet in obese mice. Our findings may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions related to the reward system and associated with uncontrolled intake of high-fat foods, thus facilitating the identification of novel therapeutic targets.

Childhood sexual abuse is associated with higher total ghrelin serum levels in adulthood: results from a large, population-based study

Ghrelin is an orexigenic peptide hormone synthesized in times of stress and hunger and alterations of the ghrelin system following acute stressors could be repeatedly shown in humans. However, little data exists on long-term effects of trauma on the ghrelin system. We aimed to investigate the influence of childhood trauma on total ghrelin serum levels in a large, population-based study. Total serum ghrelin was measured in 1666 participants of a population-based cross-sectional study (‘LIFE study’). The Childhood Trauma Screener (CTS) was used for the assessment of childhood trauma in the final sample (n = 1086; mean age: 57.10 ± 16.23 years; 632 males, 454 females). Multiple linear regression analyses and generalized linear models were chosen to examine the association between childhood trauma and total serum ghrelin concentrations. Childhood sexual abuse went along with significantly higher ghrelin serum levels in the total sample (β = 0.114, t = 3.958; p = 0.00008) and in women (β = 0.142, t = 3.115; p = 0.002), but not in men (β = 0.055; t = 1.388; p = 0.166). Women with severe emotional neglect in the childhood had higher ghrelin levels than those without (odds ratio = 1.204; p = 0.018). For the CTS Sum Score and other CTS sub-scale scores, no significant association with ghrelin serum levels was found. Our study is the first to show associations between childhood sexual trauma and total ghrelin levels in adults in a large, community-based sample. Our results should initiate further research of the role of ghrelin in human stress response in prospective study designs.

Body Weight Reduction by Bariatric Surgery Reduces the Plasma Levels of the Novel Orexigenic Gut Hormone Insulin-like Peptide 5 in Patients with Severe Obesity.

Insulin-like factor 5 (INSL5), a novel hormone secreted by the enteroendocrine cells of the distal colon, has been implicated in appetite and body weight regulation in animals given its orexigenic properties. We investigated basal INSL5 plasma levels in a group of morbidly obese subjects before and after laparoscopic sleeve gastrectomy. Furthermore, we analyzed the expression of INSL5 in human adipose tissue. Before bariatric surgery, obese subjects showed basal INSL5 plasma levels that were positively correlated with BMI, fat mass, and leptin plasma levels. After weight loss by laparoscopic sleeve gastrectomy, INSL5 plasma levels in obese subjects were significantly lower than those observed before surgery. Finally, we did not detect any expression of the INSL5 gene in human adipose tissue, both at the mRNA and protein levels. The present data show that subjects with obesity have INSL5 plasma levels positively correlating with adiposity markers. After bariatric surgery, INSL5 plasma levels decreased significantly, and this decrease was not directly due to the loss of adipose tissue since this tissue does not express INSL5. Considering the orexigenic properties of INSL5, the reduction of its plasma levels after bariatric surgery in obese subjects could participate in the still unclear mechanisms leading to appetite reduction that characterize bariatric surgery procedures.

Review: Gestational and postnatal nutritional effects on the neuroendocrine control of puberty and subsequent reproductive performance in heifers.

Pubertal attainment is an intricate biological process that involves maturation of the reproductive neuroendocrine axis and increased pulsatile release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone. Nutrition is a critical environmental factor controlling the timing of puberty attainment. Nutrient restriction during early postnatal development delays puberty, whereas increased feed intake and adiposity during this period hasten pubertal maturation by imprinting the hypothalamus. Moreover, the dam's nutrition during gestation can program the neuroendocrine system in the developing fetus and has the potential to advance or delay puberty in the offspring. Leptin, a hormone produced primarily by adipose cells, plays an important role in communicating energy status to the brain and regulating sexual maturation. Leptin's regulation of GnRH release is mediated by an upstream neuronal network since GnRH neurons do not contain the leptin receptor. Two groups of neurons located in the arcuate nucleus of the hypothalamus that express neuropeptide Y (NPY), an orexigenic peptide, and alpha melanocyte-stimulating hormone (αMSH), an anorexigenic peptide, are central elements of the neural circuitry that relay inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. Moreover, KNDy neurons, neurons in the arcuate nucleus that co-express kisspeptin, neurokinin B (NKB), and dynorphin, also play a role in the metabolic regulation of puberty. Our studies in beef heifers demonstrate that increased rates of BW gain during early postweaning (4-9 mo of age) result in reduced expression of NPY mRNA, increased expression of proopiomelanocortin and kisspeptin receptor mRNA, reduced NPY inhibitory inputs to GnRH neurons, and increased excitatory αMSH inputs to KNDy neurons. Finally, our most recent data demonstrate that nutrition of the cow during the last two trimesters of gestation can also induce transcriptional and structural changes in hypothalamic neurocircuitries in the heifer progeny that likely persist long-term after birth. Managerial approaches, such as supplementation of the dam during gestation (fetal programming), creep feeding, early weaning, and stair-step nutritional regimens have been developed to exploit brain plasticity and advance pubertal maturation in heifers.

Scd knockout activates β-oxidation of fatty acids via accumulating stearic acid (18:0) and induces anorexia in zebrafish

Stearoyl-CoA desaturase (scd) is the rate-limiting enzyme for the biosynthesis of monounsaturated fatty acids (MUFA), and it plays a critical role in regulating hepatic lipogenesis and lipid oxidation. However, its role in teleosts remains unclear. In this study, we generated scd knockout zebrafish (scd-/-) to explore the role of Scd in regulating growth and metabolism in teleosts. The results showed that scd knockout reduces hepatic lipid deposition by down-regulating the expression of lipogenesis-related genes and up-regulating the expression of lipolysis-related genes. In addition, the knockout of scd suppressed food intake and reduced body weight. Further analysis confirmed that scd knockout suppressed the feeding behavior by decreasing expression of orexigenic peptide genes and increasing expression of anorexigenic peptide genes. The high-level stearic acid (18:0) feeding experiment results showed that the accumulation of 18:0 inhibited feeding behavior, reduced food intake, decreased body weight, and increased lipid β-oxidation, which was essentially consistent with the phenotypes of scd deficiency. Taken together, our results indicate that the knockout of scd inhibited the food intake through the accumulation of 18:0. This study preliminarily reveals the role of Scd in regulating food intake of teleosts, which provides theoretical basis for the functional study of Scd.

First insights about orexigenic activity and gastrointestinal tissue localization of ghrelin from Corvina drum (Cilus gilberti)

The croaker Cilus gilberti commonly known as Corvina drum is considered a target marine species for the diversification of Chilean aquaculture. To optimize culture conditions, molecular markers for appetite regulation must be examined. Ghrelin, a gastrointestinal peptide, plays a stimulatory role in the food intake of mammals and teleost fish. Nevertheless, even though the appetite-controlling system is considered relatively well conserved among vertebrates, the bioactivity of these molecules should be analyzed in each fish species. Therefore, this study aimed to investigate the expression and orexigenic ability of C. gilberti ghrelin. After the pre and postprandial period, the stomach expression of ghrelin mRNA in juvenile C. gilberti was analyzed. The coding sequence of C. gilberti ghrelin was used to identify the mature peptide and then chemically synthesized. The orexigenic ability of acylated ghrelin (cgGhre) and non-acylated (D-cgGhre) ghrelin was tested in C. gilberti juveniles. Moreover, the blood and the gastrointestinal location of synthetic ghrelin after intraperitoneal injection were measured. The results showed that the stomach has the highest expression of ghrelin mRNA, and that ghrelin levels increased in the preprandial period and diminished after it. There were no differences in the secondary structure of D-cgGhre compared to cgGhre but the peptide with the serine acylation stabilized its unordered conformation. However, the highest cumulative feed intake occurred in fish intraperitoneally injected with cgGhre. In addition, synthetic ghrelin was maintained in the C. gilberti blood until 8 h post-injection (hpi). Finally, biotinylated ghrelin allowed localizing the synthetic peptide in digestive tissue, mainly in the stomach and pyloric caeca. The mRNA expression of the growth hormone secretagogue receptor (GHS-R), also known as the ghrelin receptor, in gastrointestinal organs supports the idea of peripheral orexigenic regulation in these tissues. In conclusion, results suggest that C. gilberti ghrelin conserves the orexigenic ability reported in other teleost fish with a regulatory role in the gastrointestinal tract (GIT) of the Corvina drum. This is the first report demonstrating the uptake and distribution of a small orexigenic peptide in the digestive tissues of a South American sciaenid. Although ghrelin is a promising molecular marker for feed intake analysis in C. gilberti culture, further research is needed to continue evaluating the effects of aquaculture practices on peripheral appetite signalizer.

Ghrelin at the interface of hunger, reward and obesity

AbstractGhrelin, a stomach-derived hunger and appetite signal, drives behaviors that ensure we seek out and consume foods, not only in situations of energy deficit but also when anticipating palatable foods. Key target pathways for ghrelin include the orexigenic agouti-related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (Arc), that appear to confer the unpleasant feelings of hunger. They also include dopamine neurones in the ventral tegmental area, where ghrelin heightens motivation for food rewards. Recently, we have employed a variety of neural circuit mapping techniques in rodents to help clarify the function of populations of ghrelin-responsive targets. We found that 1) chemogenetic activation of ghrelin-responsive cells in the Arc is sufficient to drive a feeding response and to induce food-motivated behaviour and 2) that dopamine neurones in the VTA are activated when mice are exposed to cues that predict a food reward than to its retrieval, as revealed by fiber photometry recordings from these cells. Further studies aim to determine the role of ghrelin-responsive cells in the parabrachial nucleus of the brainstem. Overall, the brain ghrelin signalling system is well positioned to integrate the response to hunger, enhanced by both intrinsic and external cues and in ways that are relevant to curb over-eating in obesity.Disclosure of InterestNone Declared

Ghrelin and Obestatin Levels as a Novel Marker in Iraqi Obese Children

Obesity is an escalating health problem in developing countries. One to ten children worldwide are overweight in a report showed by the International Obesity Task Force. Ghrelin, orexigenic peptide, has 28 amino acids, it is considered the greatest remarkable promotion in the last two decades for understanding the physiological changes of action regu­lating food intake and hunger. Obestatin is a 23-amino acid peptide nearly connected to ghrelin that secures from substitution splicing the alike resort molecule, pre-proghrelin. The study is designed to assess the level of ghrelin and obestatin in Iraqi obese children and its relation with other biochemical parameters. Ghrelin and obeststin levels were measured in sixty obese children; the range of their age was (5-16) years, and this group was compared to 30 children in a healthy state as a control. Serum FBS, PPBS, and also lipid profiles (TG, TC, HDL-c, and LDL-c) were determined in the studied groups. Calculation of insulin resistance was done by using (HOMA-IR) a Homeostasis Model assessment of insulin resistance. Ghrelin levels were lower in a significant way in subjects who have obesity in comparison with control group. Significantly, there was a high increase in obestatin in obese patients when compared with control. This study demonstrates that obestatin raises and ghrelin is low in obesity, these hormones are related to the resistance of insulin, and there is an association between ghrelin and oxidative stress. The scales between obestatin and ghrelin are likely disturbed in obesity.

Relationship Between Appetite-Related Peptides and Frailty in Older Adults

ABSTRACT Background Frailty, is a geriatric syndrome that reduces the resistance to stress situations caused by activities of daily living and increases morbidity and mortality. We hypothesized that a decrease in orexigenic peptides or an increase in anorexigenic peptides might be associated with frailty. We aimed to investigate the relationship between frailty and six appetite-related peptides: ghrelin, neuropeptide Y (NPY), agouti-related peptide (AgRP), cocaine-amphetamine-associated peptide (CART), peptide YY, and alpha MSH (α-MSH). Methods This cross-sectional study was conducted on 85 older adults who visited the outpatient clinic. All patients underwent comprehensive geriatric assessment. Frailty status was assessed using the Fried frailty index. Plasma levels of six appetite-related peptides were studied. Results The mean age was 73.7 ± 5.4 years, 27 (31.8%) of the patients were male, and 32 of the patients (37.6%) were frail. While plasma levels of ghrelin, NPY and AgRP were significantly lower in frail patients, CART and α-MSH levels were higher compared to non-frail patients (p < .05 for all). Peptide YY was found to be higher in the frail group, however, the difference did not reach statistical significance (p = .052). In multivariate logistic regression analysis, the ghrelin, AgRP, CART, and α-MSH levels were independent predictors of frailty. Moreover, a weak correlation was found between all peptides(except NPY) and handgrip strength and Lawton-Brody score. Conclusion Ghrelin, AgRP, CART, and α-MSH levels were found to be independent predictors of frailty. Our results suggest that appetite-related peptides might be playing roles in the pathogenesis of frailty. Further larger prospective studies are needed to test this hypothesis.

Ghrelin signaling in the cerebellar cortex enhances GABAergic transmission onto Purkinje cells

Ghrelin, an orexigenic peptide ligand for growth hormone secretagogue receptor 1a (GHS-R1a), occurs not only in the stomach but also in the brain, and modulates neuronal activity and synaptic efficacy. Previous studies showed that GHS-R1a exists in the cerebellum, and ghrelin facilitates spontaneous firing of Purkinje cells (PCs). However, the effects of ghrelin on cerebellar GABAergic transmission have yet to be elucidated. We found that ghrelin enhanced GABAergic transmission between molecular layer interneurons (MLIs) and PCs using electrophysiological recordings in mouse cerebellar slices. This finding was consistent with the possibility that blocking synaptic transmission enhanced the ghrelin-induced facilitation of PC firing. Ghrelin profoundly increased the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in PCs without affecting miniature or stimulation-evoked IPSCs, whereas it significantly facilitated spontaneous firing of MLIs. This facilitation of MLI spiking disappeared during treatments with blockers of GHS-R1a, type 1 transient receptor potential canonical (TRPC1) channels and KCNQ channels. These results suggest that both activating TRPC1 channels and inhibiting KCNQ channels occur downstream the ghrelin-GHS-R1a signaling pathway probably in somatodendritic sites of MLIs. Thus, ghrelin can control PC firing directly and indirectly via its modulation of GABAergic transmission, thereby impacting activity in cerebellar circuitry.

Fasting alters p75NTR and AgRP mRNA expression in rat olfactory bulb and hippocampus

Classic non-homeostatic structures involved in food intake regulation are reciprocally influenced by metabolic signals. Orexigenic peptides expressed in the olfactory bulb (OB) and hippocampus (HP) modulate olfactory processing and memory, respectively. Hypothalamic circuits also modulate feeding behavior by activating and releasing Agouti-related peptide (AgRP) in response to orexigenic signals. An adequate response to fasting requires the expression of p75 neurotrophin receptor (p75NTR) in AgRP neurons. The present study aimed to determine whether there is a role for p75NTR and AgRP in the OB and HP on the feeding behavior of fasted rats. A group of fasted rats (FG) was confronted with a decision-making paradigm in a T-maze containing a standard chow pellet (CP), and the same pellet coated with a phenolic-rich avocado paste extract (AVO) on either end; their OB and HP were then analyzed with histological and molecular tools. FG rats had briefer feeding latencies, as compared to control rats fed ad libitum (median latencies: 55.4 vs 191.7 min, p = 0.032). They also had reduced cell counts in both brain structures, as compared to satiated rats. AgRP mRNA was not expressed in the HP of either group, however, it was found in the OB. p75NTR mRNA was expressed in both brain structures of FG rats. These results suggest that contrasting metabolic states (fasted or satiated) motivate different feeding responses, which are influenced by p75NTR and AgRP mRNA expression in non-homeostatic food intake brain structures.

The Gut Microbiome Influences the Gene Expression Profile of Neuroendocrine and Enteroendocrine Systems

Objective/Hypothesis: The gut microbiome influences metabolism, but the underlying mechanisms are not completely understood. We hypothesized that the gut microbiome modulates metabolism by regulating the expression of key neuroendocrine and enteroendocrine genes such as neuropeptide Y (Npy) which is a potent brain orexigenic peptide and G-protein-coupled receptor-17 (Gpr17) which decreases incretin secretion in the gut.&#x0D; Approach: The gene expression profiles in mouse hypothalamus and gastrointestinal tract segments (duodenum, jejunum, ileum, and colon) were compared from germ-free (GF) mice (n=9 females, n=9 males) and conventional mice (n=9 females, n=9 males). Gene transcription was determined through total RNA yield extracted from the various tissues using qRT-qPCR. The data was analyzed using two-way ANOVA and unpaired t-test.&#x0D; Results: We found that RNA yield in brain and gut tissues differed in a sex and microbiome dependent manner. The medial basal hypothalamus of the female germ-free mice had lower RNA yield compared with conventional female mice (p=0.0082). In the intestine, the RNA concentrations of the germ-free mice showed a decrease from the proximal to distal gut, however, an opposite trend was observed in the conventional mice with an overall increase of concentration from the proximal to distal gut. This trend may reflect the high concentration of the microbiota in the distal gut. Regarding gene expression of the neuroendocrine and enteroendocrine systems, Npy had lower expression in the medial basal hypothalamus (MBH) of conventional males (p=0.004), Gpr17 showed moderate duodenal expression in conventional mice (p=0.029), and Gpr17 showed increased duodenal expression in germ-free females (p=0.044).&#x0D; Summary/Conclusions: With enriched microbiota in the ileum and colon, our results indicate that gut microbiota increase host gene transcription in the distal gut segments. Future studies will aim at investigating the mechanistic link between the microbiome and regulation of gene expression in neuroendocrine and enteroendocrine tissues.

The hypothalamic neuropeptide, QRFP, regulates high fat diet intake in female Long-Evans rats following ovariectomy

Obesity rates in women continue to increase throughout the lifespan and obesity-related comorbidities are prevalent in women in estrogen deficiency. The hypothalamic neuropeptide, QRFP, is an orexigenic peptide that increases the intake of high fat diet (HFD) in female rats and is overexpressed following ovariectomy (OVX). Therefore, the goal of the current series of experiments was to elucidate the effect of QRFP on HFD intake following OVX and determine if QRFP-26 administration in ovariectomized females altered expression of prepro-neuropeptide Y (NPY), agouti-related peptide (AgRP) and proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus (MBH) and prepro-orexin in the lateral hypothalamus (LH). The intake of HFD was measured following acute administration of QRFP-26 prior to or following estradiol benzoate (EB) treatment in ovariectomized females. When administered prior to EB treatment, QRFP-26 increased HFD intake. EB treatment attenuated the effects of QRFP-26 on HFD intake. Sub-chronic, continuous administration of QRFP-26 increased HFD intake and weight gain following OVX. Subchronic, continuous administration of QRFP siRNA into the 3rd ventricle via osmotic pump decreased prepro-QRFP mRNA levels in the MBH by ∼75%, decreased HFD intake and decreased weight gain following OVX. QRFP-26administration did not alter the expression of prepro-NPY, AgRP or POMC mRNA in the MBH, but decreased prepro-orexin mRNA in the LH of ovariectomized females. Overall, results from these studies support the orexigenic neuropeptide, QRFP, as an important mediator of the ingestion of highly palatable foods and subsequent weight gain in females during estrogen deficiency.