Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance

Shrestha, Yogendra B.; Wickwire, Kathie; Giraudo, Silvia Q.

doi:10.1016/j.peptides.2009.03.013

Cited by 35 publications

(24 citation statements)

References 24 publications

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“…Collectively, these observations support that ghrelin is not a regulator of food intake in rodents in standard housing conditions. In contrast, our results emphasized the role of ghrelin in fat storage, which is in agreement with previous observations supporting that both adipogenic and orexigenic roles of ghrelin are independently regulated (8,44). On the other hand, our observations are consistent with those in Ghsr -/-mice supporting that ghrelin-GHSR signal is not a key contributor to somatic growth in rodents (10).…”

Section: Discussionsupporting

confidence: 93%

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, current Ghsr knockout models cannot dissect ghrelindependent and -independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying a Ghsr mutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with the Ghsr Q343X mutation (Ghsr M/M ), which is predicted to delete the distal part of the GHSR C-terminus tail, a domain critical for the signal termination processes of receptor internalization and -arrestin recruitment. In cells, the Q343X GHSR mutant showed enhanced ligandinduced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. Ghsr M/M rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, Ghsr M/M rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions, Ghsr M/M rats showed increased body weight, adiposity and reduced glucose tolerance. Overall, our data stresses the physiological role of the distal domain of GHSR C-terminus as a suppressor of ghrelin sensitivity and we propose using the Ghsr M/M rat as a physiological model of gain-of-function in Ghsr to identify treatments for obesity-related conditions.3

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Section: Discussionsupporting

confidence: 93%

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

et al. 2016

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“…5B). A previous study demonstrated that knockdown of GHSR mRNA in this nuclei reduces body weight and blood ghrelin levels without affecting food intake (35). This suggests a divergence between energy intake and body weight and may provide a mechanism by which DIO mice maintain obesity in the absence of excess caloric intake.…”

Section: Discussionmentioning

confidence: 91%

Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons

et al. 2010

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Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.

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“…Recent studies examined the role of ghrelin in the PVN by selectively knocking down GHSRs in vivo (60% knockdown) using RNA interference. GHSR knockdown does not affect daily food intake but significantly reduces body weight and blood ghrelin levels [61]. Thus, direct ghrelin activation of GHSR in the PVN regulates body weight independently of food intake.…”

Section: Ghrelin Mediates Food Intake and Body Weight Independentlymentioning

confidence: 99%

Metabolic Status Regulates Ghrelin Function on Energy Homeostasis

Briggs

Andrews²

2010

Neuroendocrinology

108

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Ghrelin plays an important role in energy metabolism by regulating food intake, body weight and glucose homeostasis. In this review, we highlight recent developments describing how ghrelin stimulates neuropeptide Y (NPY) neurons, but not pro-opiomelanocortin neurons, to regulate food intake. We describe a novel signaling modality, in which ghrelin activates NPY/agouti-related protein (AgRP) neurons through fatty acid oxidation, reactive oxygen species buffering and mitochondrial function. We hypothesize that this unique system may serve to maintain NPY/AgRP cell function during prolonged negative energy balance. We discuss the idea that the metabolic status plays a key role in ghrelin function. For example, our recent studies illustrate that diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. On the other side of the metabolic coin, ghrelin and GOAT knockout models show that ghrelin is required to maintain blood glucose during severe calorie restriction. We propose the hypothesis that ghrelin primarily functions during negative energy balance to maintain whole-body energy homeostasis.

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Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance

Cited by 35 publications

References 24 publications

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons

Metabolic Status Regulates Ghrelin Function on Energy Homeostasis

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Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance

Cited by 35 publications

References 24 publications

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons

Metabolic Status Regulates Ghrelin Function on Energy Homeostasis

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Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Enhanced responsiveness of Ghsr ^Q343X rats to ghrelin results in enhanced adiposity without increased appetite