RESUMO
Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1-14]. For this, two experimental models were used: (i) LEAP2[1-14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1-14] or MK677. Perinatal GHSR modulation by LEAP2[1-14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.
Assuntos
Fígado , Receptores de Grelina , Animais , Fígado/metabolismo , Receptores de Grelina/metabolismo , Receptores de Grelina/genética , Feminino , Ratos , Gravidez , Masculino , Transdução de Sinais , Grelina/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Ratos Wistar , Metabolismo Energético , Maturidade Sexual/fisiologia , Glucose/metabolismo , Proteínas SanguíneasRESUMO
We evaluated glycemia and triglyceride, hepatic, muscular, and renal damage markers, redox profile, and leptin and ghrelin hormone levels in COVID-19 patients. We also conducted statistical analysis to verify the potential of biomarkers to predict poor prognosis and the correlation between them in severe cases. We assessed glycemia and the levels of triglycerides, hepatic, muscular, and renal markers in automatized biochemical analyzer. The leptin and ghrelin hormones were assessed by the ELISA assay. Severe cases presented high glycemia and triglyceride levels. Hepatic, muscular, and renal biomarkers were altered in severe patients. Oxidative stress status was found in severe COVID-19 patients. Severe cases also had increased levels of leptin. The ROC curves indicated many biomarkers as poor prognosis predictors in severe cases. The Spearman analysis showed that biomarkers correlate between themselves. Patients with COVID-19 showed significant dysregulation in the levels of several peripheral biomarkers. We bring to light that a robust panel of peripheral biomarkers and hormones predict poor prognosis in severe cases of COVID-19 and biomarkers correlate with each other. Early monitoring of these biomarkers may lead to appropriate clinical interventions in patients infected by SARS-CoV2.
Assuntos
Biomarcadores , COVID-19 , Humanos , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/mortalidade , Biomarcadores/sangue , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Grelina/sangue , Leptina/sangue , Idoso , Índice de Gravidade de Doença , SARS-CoV-2 , Triglicerídeos/sangue , Estresse Oxidativo , Glicemia/análise , Glicemia/metabolismoRESUMO
BACKGROUND: The central nucleus of the amygdala (CeA) is part of the dopaminergic reward system and controls energy balance. Recently, a cluster of neurons was identified as responsive to the orexigenic effect of ghrelin and fasting. However, the signaling pathway by which ghrelin and fasting induce feeding is unknown. AMP-activated protein kinase (AMPK) is a cellular energy sensor, and its Thr172 phosphorylation (AMPKThr172) in the mediobasal hypothalamus regulates food intake. However, whether the expression and activation of AMPK in CeA could be one of the intracellular signaling activated in response to ghrelin and fasting eliciting food intake is unknown. AIM: To evaluate the activation of AMPK into CeA in response to ghrelin, fasting, and 2-deoxy-D-glucose (2DG) and whether feeding accompanied these changes. In addition, to investigate whether the inhibition of AMPK into CeA could decrease food intake. METHODS: On a chow diet, eight-week-old Wistar male rats were stereotaxically implanted with a cannula in the CeA to inject several modulators of AMPKα1/2Thr172 phosphorylation, and we performed physiological and molecular assays. KEY FINDINGS: Fasting increased, and refeeding reduced AMPKThr172 in the CeA. Intra-CeA glucose injection decreased feeding, whereas injection of 2DG, a glucoprivation inductor, in the CeA, increased food intake and blood glucose, despite faint increases in AMPKThr172. Intra-CeA ghrelin injection increased food intake and AMPKThr172. To further confirm the role of AMPK in the CeA, chronic injection of Melanotan II (MTII) in CeA reduced body mass and food intake over seven days together with a slight decrease in AMPKThr172. SIGNIFICANCE: Our findings identified that AMPK might be part of the signaling machinery in the CeA, which responds to nutrients and hormones contributing to feeding control. The results can contribute to understanding the pathophysiological mechanisms of altered feeding behavior/consumption, such as binge eating of caloric-dense, palatable food.
Assuntos
Proteínas Quinases Ativadas por AMP , Núcleo Central da Amígdala , Ingestão de Alimentos , Jejum , Grelina , Ratos Wistar , Animais , Masculino , Grelina/metabolismo , Grelina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fosforilação/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismoRESUMO
OBJECTIVE: Diet and exercise, which are the building blocks of obesity management, provide weight loss by creating a negative energy balance. However, the effect of energy deficit induced by long-term diet and exercise on appetite hormones remains unclear. The study was designed to determine the effect of a 12-week diet and exercise program applied to obese individuals on the levels of appetite hormones, namely, ghrelin, GLP-1, and PYY. METHODS: A total of 62 obese individuals (BMI≥30) and 48 healthy controls (BMI 18.50-29.99) participated in the study. Appropriate diet (1000-1500 kcal/day) and exercise (at least 5000 steps/day) programs were applied to obese individuals according to age, gender, and BMI. The ghrelin, GLP-1, and PYY values of the participants were analyzed by the ELISA method and commercial kit by taking venous blood samples before and after 12 weeks of treatment. RESULTS: While ghrelin levels of individuals decreased significantly after diet and exercise, PYY levels increased significantly. However, despite the treatment applied, the GLP-1 and PYY levels of the case group did not reach the levels of the control group. CONCLUSION: Long-term diet and exercise intervention had a positive effect on appetite regulation hormones. It reduced ghrelin levels after treatment. Associated weight loss was facilitated. In the case group, increased satiety hormones after combined treatment supported the maintenance of body weight by increasing satiety.
Assuntos
Grelina , Peptídeo 1 Semelhante ao Glucagon , Humanos , Peptídeo YY , Obesidade/terapia , Redução de Peso/fisiologia , DietaRESUMO
PURPOSE: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations. METHODS: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB). RESULTS: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (ß: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (ß: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (ß: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (ß: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner. CONCLUSIONS: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans. TRIAL REGISTRATION: The study was retrospectively registered in clinicaltrials.gov (April 2023). CLINICALTRIALS: gov Identifier: NCT05815641.
Assuntos
Grelina , Fome , Masculino , Feminino , Humanos , Fome/fisiologia , Hepcidinas , Apetite , Obesidade , SensaçãoRESUMO
CRH neurons are found in the paraventricular nucleus(PVN) and central amygdala(CeA) nuclei. This study investigated the effects of sub-chronic CRH administration into the PVN and CeA nuclei on food intake biomarkers in rats divided into five groups: control, two shams, and two CRH-PVN and CRH-CeA groups(receiving CRH in nuclei for seven days). The CRH-PVN group had significantly higher cumulative food intake and food intake trends than the CRH-CeA group. The CRH-CeA and CRH-PVN groups exhibited significant increases in food intake during hours 1 and 2, respectively. Moreover, to be time-dependent, food intake is modulated by different brain nuclei. The CRH signaling pathway appeared to be activated later in the PVN than CeA. Both groups exhibited significantly higher leptin levels, the CRH-PVN group exhibited higher ghrelin levels and lower glucose levels. Repetitive administration of CRH into the PVN and CeA significantly reduced body weight differences. CRH administration into the PVN affected both leptin and ghrelin levels, but ghrelin had a greater impact on glucose variations and cumulative food intake than leptin. Finally, CRH administration into the PVN and CeA likely activated the HPA axis, and the CeA had a greater impact on the stress circuit than on food intake behavior.
Assuntos
Núcleo Central da Amígdala , Hormônio Liberador da Corticotropina , Ratos , Masculino , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Núcleo Central da Amígdala/metabolismo , Leptina/metabolismo , Grelina , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Ingestão de Alimentos/fisiologia , GlucoseRESUMO
Introduction: In a previous study we found that ghrelin (Ghrl) misbalance during the peri-implantation period significantly impaired fetus development. In this study we aimed to evaluate the putative mechanisms underlying these effects, including embryo implantation success, uterine nitric oxide synthase (NOS) activity, nitric oxide synthesis and the inflammatory/immune uterine profile. Methods: Ghrelin misbalance was induced by injecting 4nmol/animal/day of Ghrl (hyperghrelinemia) or 6nmol/animal/day of a Ghrl antagonist (Ant: (D-Lys3)GHRP-6) from day 3 to 8 of pregnancy. Control animals (C) were injected with de vehicle. Females were euthanized at pregnancy day 8 and their uteri excised in order to evaluate: the percentage of reabsorbed embryos (microscopically), eNOS, iNOS and nytrotirosine expression (by immunohistochemistry), nitrite synthesis (by Griess technique), VEGF, IL-10, IL-17, IL-6, MMP9 and GM-CSF expression (by qPCR) and leukocyte infiltration by flow cytometry (evaluating T cells, NK cells, granulocytes, dendritic cells and macrophages). Results: Ant-treatment significantly increased the percentage of reabsorbed embryos and the uterine expression of eNOS, iNOS and nytrotirosine. (D-Lys3)GHRP-6-treatment increased also the expression of the inflammatory cytokines IL-6, IL-17 and MMP9, and decreased that of IL-10 (anti-inflammatory). Moreover, Ant-treatment increased also the NK cells population and that of CD11b+ dendritic cells; and decreased T cells percentages. Similarly, hyperghrelinemia showed a significant increase vs. C on eNOS, iNOS and nytrotirosineuterine expression and a decrease in T cells percentages. Conclusion: Ghrl misbalance during the peri-implantation period induces pro-inflammatory changes and nitrosative stress in the gravid uterus, impairing significantly embryo implantation and/or development.
Assuntos
Interleucina-10 , Interleucina-17 , Feminino , Gravidez , Camundongos , Animais , Metaloproteinase 9 da Matriz , Grelina/farmacologia , Estresse Nitrosativo , Interleucina-6 , Implantação do Embrião , ÚteroRESUMO
INTRODUCTION: Single-nucleotide polymorphism (SNP) rs9939609 in the FTO gene has been associated with dietary intake and appetite traits, mainly in participants with obesity; however, it remains widely unexplored in normal weight participants. Thus, the aims of this study were (1) to compare the changes in subjective appetite sensations, ghrelin, and insulin concentrations according to the SNP rs9939609 T>A in FTO and (2) to compare dietary intake between rs9939609 genotype groups in normal weight young participants. METHODS: We conducted a quasi-experimental study involving 88 normal weight participants to analyze subjective perception of appetite, hormonal response for hunger and satiety, and dietary intake according to the rs9939609 SNP. Participants received a standardized single breakfast. Visual analogue scales (VAS) were utilized for assessing the subjective perception of appetite at fasting and immediately after breakfast and at 30, 60, 90, and 120 min postprandially. Glucose, lipid profile, ghrelin, and insulin were measured at fasting and at 120 min after breakfast. Dietary intake was assessed with a 3-day food record. The SNP was determined by allelic discrimination with TaqMan probes. To compare dietetic, biochemical, and the subjective appetite sensations, Student t test, ANCOVA test, and the repeated measures ANOVA were used. The linear regression model and the linear mixed model were used for the association analysis. Pearson correlation was used to test the correlation between two quantitative variables. RESULTS: A total of 88 people participated, 81.8% were female, with a mean body mass index of 21.8 ± 2.0 kg/m2 and a mean age of 20.6 ± 2.0. Genotype frequencies of the rs9939609 SNP were 52% for the TT allele and 48% for the TA/AA. The subjective perception of appetite named hunger, fullness, satiety, desire to eat, and prospective food consumption were similar between genotypes of the rs9939609. Participants with the TA/AA genotype showed a higher intake of added sugar (p = 0.039) than TT participants. No differences were found in ghrelin, insulin, glucose, or lipid parameters between genotypes. CONCLUSION: Carriers of the A allele from FTO gene SNP rs9939609 may have an increased preference for foods, specifically for added sugars.
Assuntos
Grelina , Insulina , Humanos , Feminino , Adulto Jovem , Adolescente , Adulto , Masculino , Grelina/genética , Genótipo , Glucose , Lipídeos , Açúcares , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genéticaRESUMO
The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus-independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic-pituitary-adrenal neuroendocrine axis.
Assuntos
Hormônio Liberador da Corticotropina , Grelina , Camundongos , Masculino , Animais , Hormônio Liberador da Corticotropina/metabolismo , Grelina/farmacologia , Grelina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neurônios/metabolismoRESUMO
â¢Body weight and BMI decrease in both the EG and CG groups during the period of caloric restriction. â¢For both the EG and CG groups, fat-free mass decreases during food restriction. â¢Subjects on a high-fiber diet have reduced fasting glucose and basal insulin as well as improved insulin resistance, as attested by the lower HOMA-IR index. â¢Obese women on a high-fiber diet have suppressed postprandial (after 60 min) acylated ghrelin, confirming that the diet composition influences ghrelin levels from the first day. â¢In the present study, it was possible to verify that fasting leptin concentration diminishes in obese women on a high-fiber diet. Background - Several mechanisms, including excessive hunger, account for patients' difficulties in maintaining weight loss and dietary changes after caloric restriction. Objective - To evaluate the effect of short-term high-fiber calorie-restricted diet in appetite-regulating hormones, and hunger and satiety sensations in women with obesity. In a randomized controlled trial study, thirty women with body mass index (BMI) higher than 30 kg/m2, and aged from 20 to 50 years were hospitalized following a calorie-restricted diet (1000 kcal/day) for three days. The experimental group (n=15) received high-fiber diet and the control group (n=15), conventional diet. Results - Body weight, BMI, resting energy expenditure (REE), acylated and total ghrelin, leptin, insulin and glucose, and hunger and satiety sensations were evaluated. Linear regression models with mixed effects (fixed and random effects) helped to assess the variables between the two groups and within the groups. Body weight and BMI decreased in both the experimental and control groups (P<0.001). After the high-fiber diet, postprandial acylated ghrelin (P=0.04), glucose (P<0.001), insulin (P=0.04), and leptin (P=0.03) levels as well as the HOMA-IR index (P=0.01) decreased, whereas satiety improved (P=0.02). Obese women that followed the conventional diet had increased body fat percentage (P=0.04) and lower REE (P=0.02). The two diets did not differ in terms of hunger sensation. Conclusion - A short-term high-fiber diet improves satiety sensations and metabolic parameters while suppressing postprandial acylated ghrelin (60 minutes) and maintaining the resting energy expenditure.