scholarly journals The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

2021 ◽  
Author(s):  
Candice Marion ◽  
Philippe Zizzari ◽  
Raphaël Gp Denis ◽  
Rim Hassouna ◽  
Yacine Chebani ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Growth Hormone Secretagogue Receptor ◽  
Wild Type Littermate ◽  
Littermate Control ◽  
Growth Hormone Secretagogue ◽  
Fat Accumulation ◽  
Enhanced Sensitivity ◽  
Gut Hormone ◽  
Nutrient Partitioning

The Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to wild-type littermate rats 1) as freely behaving animals and 2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fed GhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Importantly, prior to fat accumulation, male GhsrM/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2:acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof of concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

scholarly journals The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

2020 ◽  
Author(s):  
Candice Marion ◽  
Philippe Zizzari ◽  
Raphael G.P. Denis ◽  
Rim Hassouna ◽  
Yacine Chebani ◽  
...  
Keyword(s):  
Energy Intake ◽  
Automated System ◽  
Growth Hormone Secretagogue Receptor ◽  
Wild Type Littermate ◽  
Voluntary Activity ◽  
Littermate Control ◽  
Growth Hormone Secretagogue ◽  
Fat Accumulation ◽  
Gut Hormone ◽  
Nutrient Partitioning

AbstractThe Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to wild-type littermate rats 1) as freely behaving animals using an automated system to monitor simultaneously energy intake and expenditure, respiratory exchanges and voluntary activity and 2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fed GhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Finally, prior to fat accumulation GhsrM/M rats showed shifted fuel preference towards carbohydrates utilization without alterations of energy intake, energy expenditure or physical activity. Overall, the present study provides proof of concept that shifted GHSR signaling can operate a specific alteration in nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

scholarly journals Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4800-4812 ◽  
Author(s):  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Ana I. Pozo-Salas ◽  
Antonio J. Martínez-Fuentes ◽  
Luis de Lecea ◽  
...  
Keyword(s):  
Metabolic Phenotype ◽  
Somatostatin Analogue ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ancestral Gene ◽  
Ghrelin Receptor ◽  
Physiological Relevance

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

scholarly journals Mfn2 Overexpression Attenuates MPTP Neurotoxicity In Vivo

2021 ◽  
Vol 22 (2) ◽  
pp. 601
Author(s):  
Fanpeng Zhao ◽  
Quillan Austria ◽  
Wenzhang Wang ◽  
Xiongwei Zhu
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Significant Loss ◽  
Critical Event ◽  
Mitochondrial Fragmentation ◽  
Wild Type Littermate ◽  
Littermate Control ◽  
Mptp Administration

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson’s disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

scholarly journals Effect of ghrelin on glucose regulation in mice

2012 ◽  
Vol 302 (9) ◽  
pp. E1055-E1062 ◽  
Author(s):  
Shaji K. Chacko ◽  
Morey W. Haymond ◽  
Yuxiang Sun ◽  
Juan C. Marini ◽  
Pieter J. J. Sauer ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Glucose Transporter ◽  
Growth Hormone Secretagogue Receptor ◽  
Gene Expressions ◽  
Growth Hormone Secretagogue ◽  
Composite Effect ◽  
Glucose Transporter 2 ◽  
Gut Hormone

Improvement of glucose metabolism after bariatric surgery appears to be from the composite effect of the alterations in multiple circulating gut hormone concentrations. However, their individual effect on glucose metabolism during different conditions is not clear. The objective of this study was to determine whether ghrelin has an impact on glycogenolysis, gluconeogenesis, and insulin sensitivity (using a mice model). Rate of appearance of glucose, glycogenolysis, and gluconeogenesis were measured in wild-type (WT), ghrelin knockout (ghrelin−/−), and growth hormone secretagogue receptor knockout (Ghsr−/−) mice in the postabsorptive state. The physiological nature of the fasting condition was ascertained by a short-term fast commenced immediately at the end of the dark cycle. Concentrations of glucose and insulin were measured, and insulin resistance and hepatic insulin sensitivity were calculated. Glucose concentrations were not different among the groups during the food-deprived period. However, plasma insulin concentrations were lower in the ghrelin−/− and Ghsr−/− than WT mice. The rates of gluconeogenesis, glycogenolysis, and indexes of insulin sensitivity were higher in the ghrelin−/− and Ghsr−/− than WT mice during the postabsorptive state. Insulin receptor substrate 1 and glucose transporter 2 gene expressions in hepatic tissues of the ghrelin−/− and Ghsr−/− were higher compared with that in WT mice. This study demonstrates that gluconeogenesis and glycogenolysis are increased and insulin sensitivity is improved by the ablation of the ghrelin or growth hormone secretagogue receptor in mice.

scholarly journals Ghrelin in the lateral parabrachial nucleus influences the excitability of glucosensing neurons, increases food intake and body weight

2020 ◽  
Vol 9 (12) ◽  
pp. 1168-1177
Author(s):  
Caishun Zhang ◽  
Junhua Yuan ◽  
Qian Lin ◽  
Manwen Li ◽  
Liuxin Wang ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Firing Rate ◽  
Body Weight Gain ◽  
Parabrachial Nucleus ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Lateral Parabrachial Nucleus

Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.

scholarly journals Ghrelin in rat pancreatic islets decreases islet blood flow

2019 ◽  
Vol 317 (1) ◽  
pp. E139-E146 ◽  
Author(s):  
Carl Johan Drott ◽  
Petra Franzén ◽  
Per-Ola Carlsson
Keyword(s):  
Blood Flow ◽  
Insulin Response ◽  
Physiological Mechanism ◽  
Growth Hormone Secretagogue Receptor ◽  
Flow Measurements ◽  
Growth Hormone Secretagogue ◽  
Islet Blood Flow ◽  
Fasted Rats

The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

Ghrelin Based Therapy of Metabolic Diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Yuan Liang ◽  
Wenzhen Yin ◽  
Yue Yin ◽  
Weizhen Zhang
Keyword(s):  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Peptide Hormone ◽  
Endogenous Ligand ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Amino Acid Peptide

Background: Ghrelin, a unique 28 amino acid peptide hormone secreted by the gastric X/A like cells, is an endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin-GHSR signaling has been found to exert various physiological functions including stimulation of appetite, regulation of body weight, lipid and glucose metabolism, and increase of gut motility and secretion. This system is thus critical for energy homeostasis. Objective: The objective of this review is to highlight the strategies of ghrelin-GHSR based intervention for therapy of obesity and its related metabolic diseases. Results: Therapeutic strategies of metabolic disorders targeting the ghrelin-GHSR pathway involve neutralization of circulating ghrelin by antibodies and RNA spiegelmers, antagonism of ghrelin receptor by its antagonists and inverse agonists, inhibition of ghrelin O-acyltransferase (GOAT), as well as potential pharmacological approach to decrease ghrelin synthesis and secretion. Conclusion: Various compounds targeting the ghrelin-GHSR system have shown promising efficacy for intervention of obesity and relevant metabolic disorders in animals and in vitro. Further clinical trials to validate their efficacy in human being are urgently needed.

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