IL-8, MSPa, MIF, FGF-9, ANG-2 and AgRP collection were identified for the diagnosis of colorectal cancer based on the support vector machine model.

Colorectal cancer (CRC) is one of the most common cancer, and the early detection of CRC is essential to improve the survival rate of patients. To identify diagnostic markers for colorectal cancer (CRC) by screening differentially expressed proteins (DEPs) in CRC. The DEPs were initially obtained from 12 CRC samples and 12 healthy control samples, and verification analysis was performed in another 34 CRC samples and 34 normal controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment with DEPs was analyzed by the R package clusterProfiler (Version 3.2.11), and the DEP-associated protein-protein interaction (PPI) network was created from the STRING database. Additionally, Support Vector Machine (SVM) model prediction and survival analyses were conducted on the key DEPs. Preliminary screening and functional analysis showed that the DEPs mainly overrepresented in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, Rap1, Ras, and MAPK signaling pathways. The key DEPs, including AgRP, ANG-2, Dtk, EOT3, FGF-4, FGF-9, HCC-4, IL-16, IL-8, MIF, MSPa, TECK, TPO, TRAIL R3, and VEGF-D, were used to construct a custom chip. The drug-gene interaction network suggested that TPO was a key drug target. ROC curve showed the SVM diagnostic model with the DEPs IL-8, MSPa, MIF, FGF-9, ANG-2, and AgRP had better diagnostic performance with an AUC of 0.933. Survival analysis showed the expression of FGF9, TPO, TRAIL R3, Dtk, TECK and FGF4 were associated with prognosis. This study revealed the important serum proteins in the pathogenesis of CRC, which might serve as useful and noninvasive predictors for the diagnosis of CRC.

Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries.

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.

Plasma Agouti-Related Protein and Cortisol Levels in Cushing Disease: Evidence for the Regulation of Agouti-Related Protein by Glucocorticoids in Humans.

Context: Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents. Objective: We sought to determine whether there is a relationship between plasma AgRP and hypothalamic AgRP in rats and to evaluate the relationship between cortisol and plasma AgRP in humans. Methods: We retrospectively evaluated plasma AgRP levels prior to transsphenoidal surgery in 31 patients with Cushing disease (CD) vs 31 sex- and body mass index-matched controls from a separate study. We then prospectively measured plasma AgRP, before and 6 to 12 months after surgery, in a subgroup of 13 patients with CD. Plasma and hypothalamic AgRP were measured in adrenalectomized rats with and without corticosterone replacement. Results: Plasma AgRP was stimulated by corticosterone in rats and correlated with hypothalamic AgRP expression. Plasma AgRP levels were higher in patients with CD than in controls (139 ± 12.3 vs 54.2 ± 3.1 pg/mL; P < 0.0001). Among patients with CD, mean 24-hour urine free cortisol (UFC) levels were 257 ± 39 µg/24 hours. Strong positive correlations were observed between plasma AgRP and UFC (r = 0.76; P < 0.0001). In 11 of 13 patients demonstrating surgical cure, AgRP decreased from 126 ± 20.6 to 62.5 ± 8.0 pg/mL (P < 0.05) postoperatively, in parallel with a decline in UFC. Conclusions: Plasma AgRP levels are elevated in CD, are tightly correlated with cortisol concentrations, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. AgRP's role as a potential biomarker and as a mediator of the adverse metabolic consequences of CD deserves further study.

Effect of clozapine dose and concentration on fasting concentration of appetite regulating peptides.

The aim of this study is to analyze whether clozapine serum concentration may affect fasting serum levels of several appetite regulating peptides: CART, PYY(1-36), NPY, AgRP, des-acylated ghrelin, leptin and obestatin. Serum concentration of clozapine and fasting serum levels of des-acylated ghrelin, neuropeptide Y (NPY), agouti-related protein (AgRP), peptide YY (PYY(1-36)), cocaine- and amphetamine-regulated transcript (CART), leptin and obestatin were measured in 30 subjects with schizophrenia on clozapine monotherapy. Leptin concentration was negatively correlated with clozapine dose (r = -0.53, p = 0.002), while NPY concentration was negatively correlated with clozapine concentration (r = -0.55, p = 0.01). Correlations with other peptides were not significant. We cannot conclude that serum concentration of clozapine is directly associated with increased or decreased level of appetite-regulating peptides.

[CHANGES IN LIFESTYLE FACTORS AFFECT THE LEVELS OF NEUROPEPTIDES, INVOLVED IN THE CONTROL OF EATING BEHAVIOR, INSULIN RESISTANCE AND LEVEL OF CHRONIC SYSTEMIC INFLAMMATION IN YOUNG OVERWEIGHT PERSONS].

The continuous rise of overweight and obesity is a major concern for present and future healthcare management. The aim of our study was to evaluate the influence of lifestyle changes on central regulatory mechanisms of maintaining energy homeostasis, insulin resistance and chronic systemic inflammation in 18-25 year old overweight patients. The anthropometric measurements were done for each patient, including body weight, height, waist circumference (WC), hip circumference (HC), waist to hip ratio, and body mass index (BMI). Patients were divided into two groups according to their BMI. 20 males and 21 females with BMI > 25 kg/m2 were included in the first, study, group. The second, control, group consisted of 16 males and 11 females with BMI - 18.5 - 24.9 kg/m 2. Lipid profile, fasting glucose and insulin levels, HOMA-IR, TNF-α, ceruloplasmin, neuropeptides Agouti-related protein - AgRP and kokain- and amphetamine-mediated transcript - CART were examined at the beginning of the study (Day 1) and after 10 week treatment period (Day 70). During the 10 week treatment period, people in the study group underwent physical exercise programs of 40-60 minute duration three times per week, and brisk walking during the remaining days. The mean calorie expenditure during the exercise was 500 kcal/day. Each patient in the study group was given balanced, healthy diet with 20% calorie restriction from baseline diet. Our study reveled that negative energy balance caused a statistically significant decrease in AgRP, reduction of visceral fat stores, increase of HDL, reduction of TNF-α and dissolution of insulin resistance signs. Significant but not statistically significant reduction of CART level was observed after increased physical activity program and calorie restriction diet, which might play an important role in the mechanism of decreasing weight. However, further investigations are required in order to determine its place in body weight regulation.

Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing's syndrome.

CONTEXT: Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected. OBJECTIVE: The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer. DESIGN AND PARTICIPANTS: Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls. RESULTS: Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 ± 13.0 (SEM) vs 17.2 ± 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 ± 76 vs 120 ± 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS. CONCLUSIONS: Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker.

The prediction role of indexes of circulating adipokines for common anthropometric and nutritional characteristics of obesity in the obese Central European population.

AIMS: This study was designed to investigate the relationship between 8 selected adipokines (leptin, leptin receptor, adiponectin, agouti-related peptide, omentin, visfatin, adipsin and resistin), dietary composition and anthropometric parameters found in the Central European obese population. METHODS: A total of 65 unrelated obese Central European Caucasian individuals were recruited for the study. Phenotypic measurements included weight, height, BMI, lean body mass, fat mass, body fat, waist and hip circumference, waist-hip ratio (WHR) and skinfold thickness. Participants completed standardized self-reported 7-day food records. Plasma levels of leptin, leptin receptor, adiponectin, agouti-related peptide (AgRP), resistin, adipsin, omentin and visfatin were examined using ELISA. RESULTS: Multiple associations (weight, height, percentage of body fat, waist circumference, hip circumference, WHR and sum of skinfold thickness) with the circulation levels of the investigated adipokines were identified. Leptin-Leptin receptor (L-LR) levels were found to correlate with total energy intake and macronutrients while adipsin was found to strongly correlate with multiple adipokines. Furthermore, the L-LR index was found to constitute a more accurate description of the relationship between BMI and body weight than individual measurements and the Ag-LR index was found to strongly correlate with both anthropometric and dietary characteristics. CONCLUSION: Following confirmation on larger population samples and on samples of different ethnicities, the reported adipokine indexes could become a useful tool for estimating nutritional status and predicting the body composition of specific patient groups.

Alterations in downstream mediators involved in central control of eating behavior in obese adolescents submitted to a multidisciplinary therapy.

OBJECTIVE: The aim of this study was to verify the effects of a multidisciplinary therapy (24 weeks) on neurohormonal control of food intake, specifically in orexigenic (total ghrelin, agouti-related protein [AgRP], neuropeptide Y [NPY], and melanin-concentrating hormone) and anorexigenic factors (leptin, insulin, and alpha-melanocyte stimulating hormone [α-MSH]), in obese adolescents. METHODS: A total of 88 adolescents (38 boys and 50 girls), including 62 obese and 26 normal-weight, aged 15-19 years were recruited. Obese adolescents were submitted to a 24-week multidisciplinary therapy. AgRP, NPY, melanin-concentrating hormone, leptin, insulin, glucose, α-MSH, total ghrelin, and food intake were measured at three stages (at baseline, after 12 weeks, and after 24 weeks). RESULTS: At baseline, obese adolescents showed hyperleptinemia (circulating leptin levels, which were, in boys and girls, 40 and 35 times higher than in normal-weight subjects, respectively). After 24 weeks, these values decreased in all obese patients. Our results showed no differences in ghrelin levels between obese and normal-weight adolescents, in both genders. However, obese boys reduced their plasma ghrelin concentration after 24 weeks of therapy (p < .05). The multidisciplinary therapy decreased NPY and AgRP values and increased α-MSH; simultaneously with these changes there was a decrease in total food intake after 24 weeks of therapy. CONCLUSIONS: We can conclude that the multidisciplinary therapy was efficient to modulate neurohormonal control of food intake in obese adolescents.

Time-course alterations of plasma and soleus agouti-related peptide and relationship to ATP, glycogen, cortisol, and insulin concentrations following treadmill training programs in male rats.

No studies have examined the time-course changes of the appetite stimulating hormone, agouti-related peptide (AgRP), induced by exercise training. The purpose of the study was to determine the effects of short (3 weeks), moderate (9 weeks), and long-term (12 weeks) treadmill training on plasma and soleus concentrations of AgRP, as well as ATP and glycogen concentrations in soleus muscle and liver tissues. 54 Wistar male rats were randomly assigned into control (total n=27; 3 week control=10; 9 week control=8; 12 week control=9) and training (total n=27; 3 week trained=10; 9 week trained=8; 12 week trained=9). The training groups ran for 60 min/d, 5 d/wk at 25 m/min and 0% grade for 3, 9, and 12 weeks. After the last exercise session soleus muscle, liver, and plasma were collected and frozen. Results demonstrated that after 3, 9, and 12 weeks of exercise training there was an increase in plasma and soleus AgRP that declined with age. Soleus muscle glycogen was inversely related to AgRP. After 9 weeks of training there was a significant decrease and increase in plasma insulin and cortisol, respectively. Thus, as little as 3 weeks of running enhances AgRP concentration in rat soleus and plasma whereas changes in liver ATP and glycogen and soleus muscle glycogen require 9 weeks for alteration. Plasma and soleus muscle AgRP decline with age, and AgRP concentration in plasma and soleus are related to insulin, soleus ATP, and liver glycogen.

Eating disorders in adolescents: correlations between symptoms and central control of eating behavior.

The aim of this study was to verify the relationship between eating disorders (binge eating and bulimia nervosa) and body image dissatisfaction with BMI, anorexigenic and orexigenic factors in adolescents. Thirty-two adolescents, (13 obese [BMI=36.65±5.68] and 19 non-obese [BMI=22.18±3.11]), aged between 14 and 19y, were recruited. Symptoms of eating disorders were measured by self-report questionnaires (BSQ, BITE and BES). Hormones, cytokines and neuropeptides were determined by Elisa kits (Phoenix peptide). A positive correlation was found between: leptin and BES (r=.724), BSQ (r=.705) and BITE (r=.696); BMI and BES (r=.663), BSQ (r=.525) and BITE (r=.732); the same pattern was observed to insulin and TNF-α. A negative correlation was found in α-MSH and AgRP with BES, BSQ and BITE. Blood levels of hormones and neuropeptides could be the link between obesity and eating disorders in adolescents. However, it is not clear which is the cause and which is the consequence.

Regulation of food consumption during pregnancy and lactation in mice.

The aim of the present work was to assess the expression of agouti-like protein and neuropeptide Y in pregnant and lactating mice and to compare this with the leptin level and food consumption. Food consumption, blood leptin levels, and agouti-like protein and neuropeptide Y mRNA levels in the hypothalamus of C57Bl/6J mice were assessed on days 7, 13, and 18 of pregnancy and on days 10 and 21 of lactation, and in virgin females of the same ages. During pregnancy, food consumption and leptin levels decreased on day 7 and increased in day 18 of pregnancy, while neuropeptide Y mRNA levels increased on day 13 and then remained unaltered, and the agouti-like protein level increased on day 18. After parturition, food consumption continued to increase, while leptin levels and neuropeptide Y mRNA levels decreased to normal. Thus, hyperphagia in pregnancy was due to sequential activation of the expression of neuropeptide Y and agouti-like protein, while in lactation hyperphagia resulted from mechanisms not associated with changes in the expression of these neuropeptides.

Treadmill training enhances rat agouti-related protein in plasma and reduces ghrelin levels in plasma and soleus muscle.

Ghrelin and agouti-related protein (AgRP) are orexigenic peptides secreted from stomach mucosa and the arcuate nucleus of the hypothalamus, respectively. Both peptides affect feeding behavior and play a role in energy balance, glucose homeostasis, and adiposity. The purpose of the current study was to determine the effects of moderate-term (6 weeks) running regimen on resting levels of ghrelin, AgRP, adenosine triphosphate, and glycogen in soleus muscle as well as plasma concentrations of the orexigenic hormones. Eighteen adult Wistar male rats (12 weeks old, 235-255 g) were randomly assigned to training (n = 10) and control (n = 8) groups. The training group ran for 60 min/d, 5d/wk at 25 m/min and 0% grade for 6 weeks. Forty-eight hours after the last exercise session, rats were killed; and soleus muscle and plasma were collected and frozen in liquid nitrogen for later analysis. Results demonstrated that 6 weeks of treadmill exercise reduced ghrelin and increased AgRP levels in plasma. Trained rat soleus muscle had higher levels of glycogen but not adenosine triphosphate or AgRP compared with untrained controls. Data indicate that training lowers ghrelin levels in rat soleus and plasma, which is accompanied by higher plasma AgRP and soleus glycogen content.

[Food intake regulation in pregnant and lactating mice].

OBJECTIVE: Hormone leptin inhibits appetite. It decreases hypothalamic expression of orexigenic neuropeptides, agouti-related peptide (AgRP), and neuropeptide Y (NPY). Pregnancy and lactation are characterized by hyperphagia. Food intake regulation during pregnancy and lactation is poorly understood. The aim of the work was to estimate hypothalamic expression of NPY and AgRP in pregnant and suckling mice and correlate it with food intake and blood leptin level. MEASUREMENTS: Daily food intake, and levels of leptin in blood and mRNA of AgRP and NPY in hypothalamus on day 7, 13, 18 of pregnancy, 10, 21 of lactation in C57B1/6J female mice and in age-matched virgin females. RESULTS: In the course of pregnancy, food intake increased, leptin level decreased on day 7 and increased on day 18, NPY expression was increasing until day 13 and then remained unchanged, AgRP expression increased on day 18 of pregnancy. In suckling females, food intake continued to grow, but levels ofleptin and NPY and AgRP expression decresed and became equal with that in virgin females. CONCLUSION: In pregnant mice, hyperphagia results from NPY followed by AgRP expression activation, in suckling mice--from other mechanisms which are not connected with changes in expression of these neuropeptides.