Dietary quality indices modifies the effects of melanocortin-4 receptor (MC4R) rs17782313 polymorphism on cardio-metabolic risk factors and hypothalamic hormones in obese adults.

BACKGROUND: Although the Melanocortin-4 Receptor (MC4R) gene rs17782313 C/T has been consistently related to obesity risk, the interaction between MC4R polymorphism and diet quality indices on cardio-metabolic risk factors has not yet investigated. Therefore we aimed to test this hypothesis. METHODS: This cross-sectional study recruited 188 (96 males and 92 females) healthy obese adults aged 20-50 years. Diet quality indices including Healthy Eating Index-2015 (HEI-2015) and Diet Quality Index-International (DQI-I) were constructed using data from a validated food frequency questionnaire. MC4R s17782313 were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The interaction between MC4R polymorphism and diet quality indices was tested by Analysis of covariance (ANCOVA) multivariate interaction model. RESULTS: There were significant gene-diet interactions between rs17782313 and HEI-2015 (P Interaction < 0.05) in modulating low-density lipoprotein cholesterol (LDL-C) levels among female group; rare allele heterozygotes of rs17782313 had highest mean of LDL-C concentration when placed in second tertile of HEI (P < 0.05). Moreover, rs17782313 and both indices (HEI and DQI-I) had significant interaction on serum glucose concentrations, systolic and diastolic blood pressure (SBP, DBP) in males (P Interaction < 0.05); when adherence to these indices was low, the obesity risk allele was associated with serum glucose concentrations, SBP and DBP. These gene-diet interactions remained significant even after adjustment for potential confounders. CONCLUSION: Our study showed that MC4R rs17782313 interacts with adherence to the dietary quality indices (HEI and DQI-I) to influence several cardio-metabolic risk factors in obese male and females. Further large prospective studies are warranted to confirm our findings.

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.

Central and peripheral leptin and agouti-related protein during and after pregnancy in relation to weight change.

OBJECTIVE: To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to postpregnancy in relation to weight changes, fat mass and glucose metabolism. CONTEXT: With high postpartum weight retention being a risk factor in future pregnancies and of lifelong obesity, we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable. DESIGN: Women were followed for 5 ± 1 years after pregnancy and divided into two groups, weight stable and weight gain, by weight change from start of pregnancy. PATIENTS: Twenty-five women (BMI 27 ± 5 kg/m2 ) recruited at admission for elective caesarean section. MEASUREMENTS: CSF and serum levels of agouti-related protein (AgRP), leptin and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA-IR). RESULTS: S-AgRP levels during pregnancy were lower in the weight stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the weight gain group. After pregnancy, s-AgRP increased in the weight stable group but decreased in the weight gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their prepregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR. CONCLUSION: S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight.

Evaluation of CSF and plasma biomarkers of brain melanocortin activity in response to caloric restriction in humans.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF ß-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and ß-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and ß-EP declined in CSF, whereas acutely, only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Effects of central fibroblast growth factor 21 (FGF21) in energy balance.

Fibroblast growth factor 21 (FGF21) is known as a major metabolic regulator of glucose and lipid homeostasis. Continuous intracerebroventricular (i.c.v.) administration of FGF21 was found to modulate feeding and energy expenditure in rats with diet-induced obesity, suggesting a central effect by the peptide. In this context, in the present work, we studied the effects of a single central FGF21 administration (0.5-5 µg) on feeding and energy expenditure by evaluating locomotor activity, interscapular brown adipose tissue (BAT) weight, gene expression of uncoupling protein-1 (UCP-1) in BAT and plasma norepinephrine (NE) levels in Sprague-Dawley fed rats. In addition, we evaluated the effects of FGF21 on orexigenic [agouti-related peptide (AgRP) and neuropeptide Y (NPY)] and anorexigenic [cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC)] peptides, in the hypothalamus, and dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) levels in nucleus accumbens (NAc). We confirmed that central FGF21 administration induced a significant increase in food intake, possibly mediated by increased NPY and AgRP, and decreased POMC and CART gene expression. Moreover, FGF21 could modulate the motivational aspects of feeding, possibly through stimulated NAc DA levels. On the other hand, our findings of decreased locomotor activity, BAT weight, UCP-1 gene expression and plasma NE levels support a role for FGF21 in decreasing energy expenditure.

Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men.

Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin.

Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity.

Leptin and its neuronal targets, which produce proopiomelanocortin (POMC) and agouti-related protein (AgRP), regulate energy balance. This study characterized leptin, POMC, and AgRP in the cerebrospinal fluid (CSF) of 47 healthy human subjects, 23 lean and 24 overweight/obese (OW/OB), as related to BMI, adiposity, plasma leptin, soluble leptin receptor (s-OB-R), and insulin. POMC was measured since the POMC prohormone is the predominant POMC peptide in CSF and correlates with hypothalamic POMC in rodents. Plasma AgRP was similarly characterized. CSF leptin was 83-fold lower than in plasma and correlated strongly with BMI, body fat, and insulin. The relative amount of leptin transported into CSF declined with increasing BMI, ranging from 4.5 to 0.52%, consistent with a saturable transport mechanism. CSF sOB-R was 78-fold lower than in plasma and correlated negatively with plasma and CSF leptin. CSF POMC was higher in lean vs. OW/OB subjects (P < 0.001) and correlated negatively with CSF leptin (r = -0.60, P < 0.001) and with plasma leptin, insulin, BMI, and adiposity. CSF AgRP was not different in lean vs. OW/OB; however, plasma AgRP was higher in lean subjects (P = 0.001) and correlated negatively with BMI, adiposity, leptin, insulin, and HOMA (P < 0.005). Thus, CSF measurements may provide useful biomarkers for brain leptin and POMC activity. The striking negative correlation between CSF leptin and POMC could be secondary to leptin resistance and/or neuronal changes associated with obesity but may also indicate that POMC plays a primary role in regulating body weight and adiposity. The role of plasma AgRP as a neuroendocrine biomarker deserves further study.

Serum levels of AgRP protein in patients with schizophrenia on clozapine monotherapy.

AIM: Agouti-related peptide (AgRP) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism, thus leading to weight gain. The aim of the study was to find out if AgRP level in subjects with schizophrenia on clozapine monotherapy is higher compared with healthy controls. METHODOLOGY: We determined fasting serum AgRP levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition analysis. RESULTS: There was no difference for AgRP levels between patients taking clozapine and control group (15.00±8.65 vs. 15.33±6.82 pg/mL, p =0.37). We found negative correlations between AgRP levels and total body fat (r =-0.34 and -0.48 in the whole study group and clozapine group, respectively) and positive correlations with lean body mass (r =0.38 and 0.49 in the whole study group and clozapine group, respectively), body water (r =0.34 and 0.49 in the whole study group and clozapine group, respectively) and basal metabolic rate (r =0.42 both in the clozapine and control groups). There were no correlations with age, height, weight, body mass index, fat mass index, abdominal, waist or hip circumferences, waist-hip ratio, blood pressure, total cholesterol, HDL, LDL, triglycerides, uric acid, glucose, insulin, clozapine dose or treatment duration, duration of treatment with antipsychotics and markers for insulin resistance. CONCLUSION: We cannot conclude that treatment with clozapine is associated with increased level of AgRP. We did not find previously described differences in AgRP levels between obese and non-obese subjects or associations between AgRP and various metabolic parameters.

[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.

Aerobic training (AT) is more effective than aerobic plus resistance training (AT+RT) to improve anorexigenic/orexigenic factors in obese adolescents.

BACKGROUND: The regulation of energy balance is influenced by physical exercise. Although some studies show a stimulation of hormones related to food intake, others show that exercise provides satiety. AIM: The aim of this study was to compare the effects of aerobic training (AT) and aerobic plus resistance training (AT+RT) on anorexigenic and orexigenic factors in obese adolescents undergoing interdisciplinary weight loss therapy. METHODS: A total of 26 obese adolescents, aged 15-19 years with BMI≥P95 were submitted to 12 months of interdisciplinary intervention (clinical support, nutrition, psychology and physical exercise) and divided into two groups, aerobic training (AT) (n=13) or aerobic plus resistance training (AT+RT) (n=13), which were matched according to gender and body mass. Blood samples were collected to analyze orexigenic factors (AgRP, NPY, MCH) and the anorexigenic factor alpha-MSH. RESULTS: The AT and AT+RT groups significantly reduced body mass, body mass index and body fat mass (kg) during the therapy. The AT group showed no significant changes in body lean mass (kg), whereas the AT+RT group showed an increase in body lean mass (kg) during the interdisciplinary intervention. There was an increase in AgRP levels (ng/ml) only in the AT+RT group after 6 months of interdisciplinary intervention compared with baseline condition. Conversely, α-MSH levels (ng/ml) increased only in the AT group after 12 months of interdisciplinary intervention compared with baseline condition. CONCLUSION: Aerobic training (AT) as part of an interdisciplinary therapy is more effective than aerobic plus resistance training (AT+RT) to improve secretion of anorexigenic/orexigenic factors in obese adolescents.

Trajectories of agouti-related protein and leptin levels during antipsychotic-associated weight gain in patients with schizophrenia.

OBJECTIVE: Some but not all second-generation antipsychotics can induce considerable weight gain and metabolic syndrome. Although the exact biochemical mechanisms for these adverse effects are unclear, appetite-regulating neuropeptides of the central nervous system are thought to be implicated in this process. The hypothalamic mediator Agouti-related protein (AGRP) is inhibited by leptin and was shown to increase food intake. The aim of the present study was to investigate the trajectory of AGRP levels during antipsychotic-induced weight gain. METHODS: As part of a controlled prospective clinical study, we determined indicators of body fat mass, plasma AGRP, and leptin levels in 16 patients with schizophrenia treated with ziprasidone and 21 patients with schizophrenia treated with olanzapine. Measurements by enzyme-linked immunosorbent assay were obtained before treatment (T0), after 4 weeks (T1), and after 3 months (T2) of treatment. RESULTS: Whereas body mass index and leptin levels increased in patients treated with olanzapine compared to patients treated with ziprasidone, plasma AGRP levels did not differ among the treatment groups and did not change over time. Associations between AGRP and fat mass as well as appetite were disrupted in the olanzapine-treated patients but not in the ziprasidone group. CONCLUSION: Future studies are needed to test whether the lack of a decrease in AGRP levels during weight gain in patients treated with olanzapine could perpetuate adverse metabolic long-term effects.

Agouti-related protein in patients with acute and weight-restored anorexia nervosa.

BACKGROUND: An imbalance in appetite-regulating neuropeptides of the central nervous system has been associated with anorexia nervosa (AN), but the mechanisms of action are poorly understood. Agouti-related protein (AGRP), an orexigenic mediator of the hypothalamus, increases food intake and decreases energy expenditure in times of negative energy balance. The aim of the present study was to investigate AGRP in acute and fully weight-restored patients with AN, as well as during weight gain. METHOD: Plasma AGRP and leptin levels were assessed using an enzyme-linked immunosorbent assay kit in a total of 175 female participants, including 75 patients with acute AN, 37 weight-restored AN patients and 63 healthy controls. Of the patients with acute AN, 33 were reassessed after partial weight gain. RESULTS: In weight-restored AN patients plasma AGRP levels were similar to those in healthy controls, whereas in patients with acute AN, AGRP was elevated. AGRP was inversely correlated with indicators of undernutrition such as body mass index and plasma leptin. In addition, AGRP levels normalized during weight gain of longitudinally assessed AN patients. CONCLUSIONS: Our results underline the significance of undernutrition and hypoleptinemia for the interpretation of peripheral AGRP concentrations. This provides support for the hypothesis that abnormal AGRP plasma levels in AN patients reflect undernutrition, rather than disease-specific traits.

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.

Pregnancy-specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation.

INTRODUCTION: Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. METHODS: Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 ±â€…1.1 weeks; N = 24), scheduled cesarean section (39.2 ±â€…0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. RESULTS: Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 ±â€…0.1 vs 1.7 ±â€…0.2; P < 0.0001) and remained unchanged at term (0.9 ±â€…0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 ±â€…7.8 vs 67.5 ±â€…5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. CONCLUSIONS: Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.

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.

Altered features of neurotransmitters: NPY, α-MSH, and AgRP in type 2 diabetic patients with hypertension.

OBJECTIVE: To investigate the features of neuropeptide Y (NPY), α-melanocyte stimulating hormone (α-MSH), and agouti-related protein (AgRP) in type 2 diabetes mellitus (T2DM) patients with hypertension. METHODS: Patients with T2DM (n = 384) and healthy volunteers (n = 80) were enrolled into this study. Serum NPY, α-MSH, and AgRP levels were detected using ELISA. RESULTS: Significantly higher NPY and lower α-MSH and AgRP levels were observed in patients with diabetes compared with those without diabetes, and the mean NPY levels increased, while α-MSH and AgRP levels decreased, with the development of hypertension compared with diabetic patients without hypertension. α-MSH and AgRP levels decreased with an increase in blood pressure in hypertension compared with the non-hypertension patients. Multiple stepwise linear regression analysis showed that NPY, α-MSH, and AgRP levels were closely associated with blood pressure and glucose control. Receiver operating characteristic (ROC) curve analyses indicated that α-MSH may be a better marker compared with NPY and AgRP for regulating glucose and blood pressure and to distinguish between T2DM patients with and without hypertension. CONCLUSION: NPY, α-MSH, and AgRP might play different roles and be closely related to the occurrence and development of diabetes and hypertension.

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.

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.

Serum agouti-related protein (AgRP) levels in bipolar disorder: Could AgRP be a state marker for mania?

Orexigenic and anorexigenic peptides, especially agouti-related protein (AgRP) and leptin, play important roles in the regulation of energy homeostasis in bipolar disorder. AgRP regulates energy metabolism by increasing appetite and decreasing energy expenditure. The resting energy expenditures of patients with manic bipolar disorder are higher than those of controls. Due to the effects of AgRP on energy expenditure and the increased physical activity of manic patients, we hypothesised that serum AgRP levels may be lower in manic patients than in euthymic patients and controls. There was a total of 112 participants, including 47 patients in the manic group, 35 patients in the euthymic group and 30 healthy controls. For this study, serum AgRP, leptin, cholesterol, and cortisol levels were measured and compared between the groups. The serum AgRP, leptin, and cholesterol levels were significantly different between the groups. The serum AgRP levels of manic group were significantly lower than those of euthymic and control groups. The lower serum AgRP levels of manic patients could be indicators of impaired energy homeostasis during manic episodes. Since the serum AgRP levels of manic patients are lower than those of euthymic patients and controls, AgRP could be a state marker for manic episodes.

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.