Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation

Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. Trials aiming to improve the function of transplanted islets have also been challenging. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. The therapeutic effects of DLS were assessed in terms of the expression/production of endocrine genes/proteins, insulin-releasing function under glucose stimulation of mouse islets, and outcomes of syngeneic murine islet transplantation with systemic DLS administration. DLS treatment promoted insulin production and suppressed somatostatin production, suggesting that cancelation of the binding between ghrelin and GHS-R1a on β or δ cells improved insulin expression. DLS also promoted the glucose-dependent insulin-releasing function of β cells. However, the therapeutic effect of DLS in islet transplantation was fractional. In conclusion, the GHS-R1a antagonist showed preferable effects in improving the therapeutic outcomes of islet transplantation, including the promotion of insulin-releasing function.

Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor–dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.

Traceable Peptidic Ligands that Target Ghrelin Receptors

: Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and its cognate receptor using traceable ligands is crucial in elucidating the localization, functions, and expression pattern of the peptide’s signaling pathway. Here 12 representative radio- and fluorescently-labeled peptide-based ligands are reviewed for in vitro and in vivo imaging studies. In particular, the focus is on their structural features, pharmacological properties, and applications in further biochemical research.

Neurochemical mechanisms and pharmacology of ghrelins

The purpose of the review was to analyze the neurochemical and neurophysiological mechanisms of the ghrelin system and the role of ghrelin in body functions and behavior. The focus is on the participation of ghrelin in the mechanisms of reinforcement and the formation of addictive behavior. At the beginning of the review a history of the first works on the field of ghrelin and its receptor was described. Then, genetic control, molecular precursor of ghrelin, molecular forms of ghrelin and ghrelin receptor were represented. In particular, the distribution of the ghrelin receptor, ghrelin-producing cells in the brain and its participation in various physiological functions of the body were shown. The hypothalamic functions of ghrelin were discussed: energy balance, regulation of glucose metabolism, stimulation of eating behavior, regulation of hypophys-pituitary axis (HPA) system. The connection of ghrelin with the brain CRH system was demonstrated. In particular, activation of HPA was described as a possible mechanism through which ghrelin regulates a number of physiological processes. Extrahypothalamic action of ghrelin was shown on the basis of the mechanisms of reinforcement and addiction. On the basis of their own data and literary, it was concluded that action of alcohol and psychoactive drugs are reduced after the ghrelin receptors blockade. In particular, it has been demonstrated that alcoholization of mothers affects the activity of the ghrelin system during the prenatal and early postnatal periods of development in the offspring of rats. It was shown the participation of ghrelin in memory and learning. The further perspective of the study and practical application of ghrelin-based pharmacological agents was analyzed.

The effect of a synbiotic on blood biochemistry and concentrations of leptin, ghrelin and their receptors in prepubertal rats consuming a diet containing excessive fat

Цель работы - изучить возможности патогенетической коррекции синбиотиком метаболических нарушений, вызванных чрезмерным потреблением жиров и оценить уровень лептина, грелина и их рецепторов. Методика. В работе использовалось второе поколение лабораторных крыс линии Вистар препубертатного возраста, находившихся на диете с избыточным содержанием жиров (51% от общего рациона). В возрасте 5 нед. в рацион экспериментальной подгруппы включали синбиотик, по достижению 7-недельного возраста животных выводили из эксперимента декапитацией с последующим забором материала для бактериологических, биохимических и иммуноферментных исследований. Результаты. Показано, что избыточное потребление жиров способствует росту условно-патогенной микробиоты, снижению содержания лакто- и бифидобактерий в толстом кишечнике и развитию дислипидемии. Наблюдается статистически значимое повышение уровня лептина в сыворотке крови на 49,9 %. В жировой ткани отмечено увеличение количества рецепторов к лептину ( в два раза) и грелину (на 28,2%). После коррекции синбиотиком положительная динамика отмечалась со стороны микробиоты, липидного профиля, снижался уровень лептина в сыворотке крови и рецепторов к грелину в жировой ткани. Заключение: синбиотик способствует нормализации микробиоты желудочно-кишечного тракта, липидного профиля и уровня пептидных гормонов, ответственных за чувство голода и насыщения. The aim of the study was to evaluate a possibility of using synbiotics for pathogenetic correction of metabolic disorders induced by excessive consumption of fat and to measure levels of leptin, ghrelin, and their receptors. Methods. Experiments were conducted on the second generation of prepubertal Wistar rats consuming a diet with excessive fat (51% of diet). A synbiotic was included into the diet of a rat group aged 5 weeks. At age of 7 weeks, animals of the experimental and control groups were decapitated and samples were taken for bacteriological, biochemical, and enzyme immunoassay studies. Results. Excessive fat consumption resulted in growth of conditionally pathogenic microbiota, decreased levels of lacto- and bifidobacteria in the large intestine and feces, and development of dyslipidemia. Also, serum level of leptin was increased by 49.9%, ghrelin receptor density in adipose tissue was increased by 28.2%, and leptin receptors density in adipose tissue was increased twofold. The synbiotic treatment resulted in beneficial changes of the microbiota and lipid profile; serum level of leptin and ghrelin receptors density in adipose tissue decreased. Conclusion: The synbiotic drug normalized the gastrointestinal microbiota, lipid profile, and peptide hormones responsible for feelings of hunger and satiety.

295 Awardee Talk: Novel regulation of growth hormone by kisspeptin

Kisspeptin (KP) is critical regulator of reproductive function through it’s potent stimulation of gonadotropin releasing hormone (GnRH). In addition there has been inconclusive evidence to suggest intravenous KP can stimulate growth hormone (GH). Studies in 24 h fasted (but not fed) sheep determined that ICV injection of Kp-10 can increase plasma GH concentrations. This led to questions about the mechanism linking KP and GH. Since fasting is a critical requirement for the Kp effect on GH, studies were focused on factors that are linked to fasting within the hypothalamus and are known regulators of GH. Fasting causes a major upregulation of neuropeptide Y (NPY), a potent appetite regulator and in ruminants, a stimulator of GH. Pretreatment of BIBO 3304, an NPY receptor antagonist, blocked the effect of KP to increase GH and implicated NPY as a mediator of the KP effect. Indeed, KP injected ICV upregulated cFOS in NPY and GH Releasing Hormone (GHRH) cells in the arcuate nucleus and reduced cFOS in Somatostatin (SS) cells in the periventricular nucleus. Another factor, altered by fasting and capable of regulating GH, is Ghrelin. Both blockage of Ghrelin release and central blockade of Ghrelin receptors reduced or blocked release of GH after KP treatment. These experiments suggest an hypothesis that fasting upregulates central Ghrelin and NPY expression permitting the activation of NPY by KP. NPY in turn activates GHRH and inhibits SS to release GH.