In Search of Small Molecules That Selectively Inhibit MBOAT4

Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.

Diagnostic Value of Acyl-Ghrelin in Type 2 Diabetic Patients with Non-Alcoholic Fatty Liver Disease

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the most leading cause of chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is described as one of the most significant risk factors for developing NAFLD, non-alcoholic steatohepatitis, and advanced cirrhosis. The high incidence of NAFLD in T2DM patients, as well as its serious clinical consequences, is both reasons for concern. Therefore, it is becoming critically needed to develop simple, low-cost, and noninvasive test for diagnosis and management of NFLD. Accordingly, the objective of this study was to examine the diagnostic value of acyl ghrelin (AG) for detecting NAFLD in T2D patients. AIM: The aim of this study is to examine the accuracy of AG as a non-invasive biomarker to effectively diagnose diabetic patients with NAFLD. PATIENTS AND METHODS: A total of 61 patients with T2D were selected from internal medicine outpatient clinic in National Research Centre, Egypt. 29 diabetic patients were free of NAFLD while the other 32 were diagnosed with NAFLD. Measurements of Lipid profile, fasting glucose, liver enzyme activities, and AG levels were collected. Data management and analysis were performed using SPSS version 20. RESULTS: A comparison between diabetic subjects with and without NAFLD showed some metabolic abnormalities including central obesity, significant increases in waist circumference, body weight, fasting blood sugar, triglycerides, low-density lipoprotein, liver enzymes levels, and a significant decrease in high-density lipoprotein in diabetic with NAFLD patients. Increases in total cholesterol and AG levels were observed; however, none of these differences were significant when compared with control diabetic subjects. CONCLUSIONS: The association between elevated AG level and NAFLD is clearly supported by the current findings. However, more studies are needed to consider it as diagnostic marker in NAFLD patients with T2D.

Ghrelin, Growth Hormone, and Insulin-like Growth Factor-I Levels in People With Protein C Deficiency

Acyl ghrelin (AG) is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor and exogenous AG is a strong stimulator of GH secretion [1]. The role of endogenous AG has not yet been unraveled and its regulation is complex, but it is widely accepted that circulating levels of ghrelin correlate inversely with body mass index [2]. The peptide known as unacylated ghrelin (UAG) is both a precursor to AG and one of the split products, when AG is deacylated during its degradation, so increased turnover of AG results in higher levels of UAG [3].

Yeokwisan, a Standardized Herbal Formula, Enhances Gastric Emptying via Modulation of the Ghrelin Pathway in a Loperamide-induced Functional Dyspepsia Mouse Model

Background: Yeokwisan, a standardized herbal formula, has exhibited clinical benefit for patients suffering from refractory functional dyspepsia (FD) in Korea since 2016. However, data about the mechanism of action of this formula are yet not available.Aim of the study: To evaluate and explore the effects of Yeokwisan on gastric emptying, a major symptom of functional dyspepsia, and its underlying mechanisms of action using a mouse model.Materials and methods: BALB/C mice were pretreated with Yeokwisan (100, 200, and 400 mg/kg, po) or mosapride (3 mg/kg, po) for 5 days and then treated with loperamide (10 mg/kg, ip) after 20 h of fasting. A solution of 0.05% phenol red (500 μL) or diet of 5% charcoal (200 μL) was orally administered, followed by assessment of gastric emptying or intestinal transit. Plasma acyl-ghrelin (ELISA), C-kit (immunofluorescence and western blotting), nNOS (western blotting) and gastric contraction- and ghrelin-related gene/protein expression levels were examined in stomach and small intestine tissues.Results: Loperamide injection substantially delayed gastric emptying, while Yeokwisan pretreatment (especially 200 and 400 mg/kg Yeokwisan) significantly attenuated this peristaltic dysfunction, as evidenced by the quantity of phenol red retained in the stomach (p < 0.05 or 0.01) and stomach weight (p < 0.05 or 0.01). The levels of plasma acyl-ghrelin and expression of gastric ghrelin-related genes, such as growth hormone secretagogue receptor (GHSR), ghrelin-O-acyltransferase (GOAT), adrenergic receptor β1 (ADRB1) and somatostatin receptor (SSTR), were significantly normalized (p < 0.05 or 0.01) by Yeokwisan (400 mg/kg). Yeokwisan (400 mg/kg) significantly tempered the loperamide-induced alterations in the c-kit and nNOS levels (p < 0.01) as well as the expression of contraction- and ghrelin-related genes, such as 5-HT4 receptor (5-HT4R), anoctamin-1 (ANO1), ryanodine receptor 3 (RYR3) and smooth muscle myosin light chain kinase (smMLCK), in the stomach, but not in the small intestine.Conclusion: The present results showed the clinical relevance of Yeokwisan, in treating FD, especially in promoting gastric emptying but not small intestinal transit. The main mechanisms corresponding to these effects may involve the modulation of the ghrelin pathway and activation of interstitial cells of Cajal in stomach tissue.

The growth hormone–insulin like growth factor axis in pregnancy

The growth hormone (GH)–insulin-like growth factor (IGF) axis is one of the main drivers of mammalian growth and development. Pituitary secretion of GH is pulsatile and under positive and negative hypothalamic control, as well as stimulation from gastric-secreted acyl-ghrelin. GH has anabolic and metabolic effects both directly via the GH-receptor (GHR) and indirectly via stimulation of IGF1 production at multiple target tissues. In this review, we describe the major changes to this axis during pregnancy, with increasing GH abundance in the maternal circulation across multiple species. This stimulates secretion of IGFs, whose bioavailability is also increased by proteolytic cleavage of their circulating binding proteins during pregnancy. These changes in turn induce maternal metabolic adaptations to pregnancy and promote placental function and fetal growth, as does exogenous GH or IGF treatment in animal models of normal and compromised pregnancy. Finally, we explore alternative approaches to enhance maternal GH abundance during pregnancy to promote maternal adaptations, placental function and hence fetal growth.

Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice

Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN (n = 225) and partially recovered (n = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group (n = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior.

Ghrelin Response to Acute and Chronic Exercise: Insights and Implications from a Systematic Review of the Literature

Background Ghrelin is a peptide hormone predominantly produced by the stomach. It exerts a wide range of functions including stimulating growth hormone release and regulating appetite, food intake, and glucose and lipid metabolism. Since physical exercise affects all these aspects, a particular interest is accorded to the relationship between ghrelin and exercise. This systematic review aimed to summarize the current available data on the topic for a better understanding of the relationship. Methods An extensive computerized search was performed in the PubMed and SPORTDiscus databases for retrieving relevant articles. The search contained the following keywords: ghrelin, appetite-related peptides, gastrointestinal peptides, gastrointestinal hormones, exercise, acute exercise, chronic exercise, training, and physical activity. Studies investigating the effects of acute/chronic exercise on circulating forms of ghrelin were included. Results The initial search identified 840 articles. After screening, 80 articles were included. Despite a heterogeneity of studies and a variability of the findings, the review suggests that acute exercise suppresses acyl ghrelin production regardless of the participants and the exercise characteristics. Long- and very long-term exercise training programs mostly resulted in increased total and des-acyl ghrelin production. The increase is more noticeable in overweight/obese individuals, and is most likely due to weight loss resulting from the training program. Conclusion The review suggests that exercise may impact ghrelin production. While the precise mechanisms are unclear, the effects are likely due to blood flow redistribution and weight loss for acute and chronic exercise, respectively. These changes are expected to be metabolically beneficial. Further research is needed for a better understanding of the relationship between ghrelin and exercise.

Effects of des-acyl ghrelin on insulin sensitivity and macrophage polarization in adipose tissue

Background and Objectives Obesity is the accumulation of adipose tissue caused by excess energy in the body, accompanied by long-term chronic low-grade inflammation of adipose tissue. More than 50% of interstitial cells in adipose tissue are macrophages, which produce cytokines closely related to insulin resistance. Macrophage biology is driven by two polarization phenotypes, M1 (proinflammatory) and M2 (anti-inflammatory). This study aimed to investigate the effect of gastric hormone des-acyl ghrelin (DAG) on the polarization phenotype of macrophages and elucidate the role of macrophages in adipose tissue inflammation and insulin sensitivity and its molecular mechanism. Methods Mice were subcutaneously administrated with DAG in osmotic minipumps. The mice were fed a normal diet or a high-fat diet (HFD). Different macrophage markers were detected by real-time revere transcription polymerase chain reaction. Results Exogenous administration of DAG significantly inhibited the increase of adipocyte volume caused by HFD and reduced the number of rosette-like structures in adipose tissue. HFD in the control group significantly increased M1 macrophage markers, tumor necrosis factor α (TNFα), and inducible NO synthase (iNOS). However, these increases were reduced or even reversed after DAG administration in vitro. The M2 markers, macrophage galactose type C-type Lectin-1 (MGL1), arginase 1 (Arg1), and macrophage mannose receptor 1 (MRC1) were decreased by HFD, and the downward trend was inhibited or reversed after DAG administration. Although Arg1 was elevated after HFD, the fold increase after DAG administration in vitro was much greater than that in the control group. Conclusion DAG inhibits adipose tissue inflammation caused by HFD, reduces infiltration of macrophages in adipose tissue, and promotes polarization of macrophages to M2, thus alleviating obesity and improving insulin sensitivity.

The endocrine effects of bitter tastant administration in the gastrointestinal system - Intragastric versus intraduodenal administration

Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill". However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1µmol/kg), QHCl (10µmol/kg) or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min prior to administration and every 10 min after administration for a period of 2 hours. Hunger was rated at the same timepoints on a visual analogue scale (VAS). ID bitter administration did not affect hunger sensations, motilin or acyl-ghrelin release compared with its PLC infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50-70 minutes after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 minutes before food intake.