Metabolic insights from a GHSR-A203E mutant mouse model

Torz, Lola; Osborne-Lawrence, Sherri; Rodríguez, Juan; He, Zhenyan; Cornejo, María Paula; Mustafá, Emilio Román; Jin, Chunyu; Petersen, Natalia; Hedegaard, Morten A; Nybo, Maja L; Damonte, Valentina Martínez; Metzger, Nathan P.; Mani, Bharath K.; Williams, Kevin W.; Raingo, Jesica; Perelló, Mario; Holst, Birgitte; Zigman, Jeffrey M.

doi:10.1016/j.molmet.2020.101004

Cited by 33 publications

(35 citation statements)

References 59 publications

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“…More specifically, ghrelin-KO mice exhibit a progressive decline in fasting blood glucose to the point of near-death following a week-long caloric restriction regimen that provides 40% of usual daily calories and depletes body fat to <2% [ 85 ]. Hypoglycemia under this regimen also occurs in mice with ablated ghrelin cells, GOAT-KO mice, GHSR-null mice, mice with ghrelin cell-selective deletion of β 1 -adrenergic receptors (which exhibit impaired ghrelin secretion), mice carrying a GHSR mutation (A203E) that ablates its constitutive activity, mice overexpressing LEAP2, and mice with hepatocyte-selective GH receptor deletion [ 9 , 27 , 77 , 83 , [86] , [87] , [88] ]. Under the severe caloric restriction regimen, ghrelin release is stimulated in wild-type mice, which in turn induces GH release, followed by activation of hepatocyte GH receptors, stimulation of autophagy in the liver, and then enhanced gluconeogenesis [ 88 , 89 ].…”

Section: Data Supporting a Role For The Endogenous Ghrelin System In The Development Of Diabetesmentioning

confidence: 99%

“…In particular, we and others have hypothesized that the endogenous ghrelin system serves an essential function during extreme nutritional and psychological challenges to defend blood glucose, protect body weight, and ultimately allow survival [ 4 ]. Highlighting these protective actions of ghrelin, ghrelin-KO mice and related genetic models that decrease ghrelin/GHSR signaling experience marked hypoglycemia and increased mortality upon exposure to a prolonged caloric restriction regimen that depletes body fat to <2%, as mentioned above [ 9 , 27 , 77 , [85] , [86] , [87] , [88] , [89] ]. Ghrelin prevents hypoglycemia from occurring in fasted, beta blocker-treated 3-week-old mice, modeling the hypoglycemia occasionally experienced by beta blocker-treated human infants and toddlers when they have not been eating [ 9 ].…”

Section: Theoretical Downsides To Modulating the Ghrelin System As A Means To Treat Obesity And Diabetesmentioning

confidence: 99%

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“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Gupta

Ogden

Shankar

et al. 2021

Molecular Metabolism

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Background The hormone ghrelin stimulates food intake, promotes adiposity, increases body weight, and elevates blood glucose. Consequently, alterations in plasma ghrelin levels and the functioning of other components of the broader ghrelin system have been proposed as potential contributors to obesity and diabetes. Furthermore, targeting the ghrelin system has been proposed as a novel therapeutic strategy for obesity and diabetes. Scope of review The current review focuses on the potential for targeting ghrelin and other proteins comprising the ghrelin system as a treatment for obesity and diabetes. The main components of the ghrelin system are introduced. Data supporting a role for the endogenous ghrelin system in the development of obesity and diabetes along with data that seemingly refute such a role are outlined. An argument for further research into the development of ghrelin system-targeted therapeutic agents is delineated. Also, an evidence-based discussion of potential factors and contexts that might influence the efficacy of this class of therapeutics is provided. Major conclusions It would not be a “leap to” conclusions to suggest that agents which target the ghrelin system – including those that lower acyl-ghrelin levels, raise LEAP2 levels, block GHSR activity, and/or raise desacyl-ghrelin signaling – could represent efficacious novel treatments for obesity and diabetes.

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Section: Data Supporting a Role For The Endogenous Ghrelin System In The Development Of Diabetesmentioning

confidence: 99%

Section: Theoretical Downsides To Modulating the Ghrelin System As A Means To Treat Obesity And Diabetesmentioning

confidence: 99%

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Gupta

Ogden

Shankar

et al. 2021

Molecular Metabolism

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“…The extracellular single unit recordings from in vitro slices indicated that ghrelin excited 73% of neurons in the ventromedial ARC, where NPY neurons are dominant, in adult rats ( 27 ). Ex vivo whole-cell patch-clamp recordings showed that ghrelin depolarized 40% of GFP-labeled arcuate NPY neurons in brain slices from 8–12 week-old male NPY-humanized Renilla reniformis green fluorescent protein transgenic mice ( 28 ). Ghrelin increased [Ca 2+ ] i in 59% of single ARC NPY neurons ( 9 ) and in 21–41% of single ARC neurons ( 12 , 25 ) in 5–7 week-old male mice.…”

Section: Discussionmentioning

confidence: 99%

Ninjin'yoeito Targets Distinct Ca2+ Channels to Activate Ghrelin-Responsive vs. Unresponsive NPY Neurons in the Arcuate Nucleus

et al. 2020

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Appetite loss or anorexia substantially deteriorates quality of life in various diseases, and stand upstream of frailty. Neuropeptide Y (NPY) in the hypothalamic arcuate nucleus (ARC) and ghrelin released from stomach are potent inducers of appetite. We previously reported that Ninjin'yoeito, a Japanese kampo medicine comprising twelve herbs, restores food intake, and body weight in cisplatin-treated anorectic mice. Furthermore, Ninjin'yoeito increased cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in not only ghrelin-responsive but ghrelin-unresponsive NPY neurons in ARC. The cellular lineage/differentiation of ghrelin-unresponsive neuron is less defined but might alter along with aging and diet. This study examined the occupancy of ghrelin-unresponsive neurons among ARC NPY neurons in adult mice fed normal chow, and explored the mechanisms underlying Ninjin'yoeito-induced [Ca 2+ ] i increases in ghrelin-unresponsive vs. ghrelin-responsive NPY neurons. Single ARC neurons were subjected to [Ca 2+ ] i measurement and subsequent immunostaining for NPY. Ghrelin failed to increase [Ca 2+ ] i in 42% of ARC NPY neurons. Ninjin'yoeito (10 μg/ml)-induced increases in [Ca 2+ ] i were abolished in Ca 2+ free condition in ghrelin-responsive and ghrelin-unresponsive ARC NPY neurons. Ninjin'yoeito-induced [Ca 2+ ] i increases were inhibited by N-type Ca 2+ channel blocker ω-conotoxin in the majority (17 of 20), while by L-type Ca 2+ channel blocker nitrendipine in the minority (2 of 23), of ghrelin-responsive neurons. In contrast, Ninjin'yoeito-induced [Ca 2+ ] i increases were inhibited by nitrendipine in the majority (14 of 17), while by ω-conotoxin in the minority (8 of 24), of ghrelin-unresponsive neurons. These results indicate that ghrelin-unresponsive neurons occur substantially among NPY neurons of ARC in adult mice fed normal chow. Ninjin'yoeito preferentially target N-type and L-type Ca 2+ channels in the majority of ghrelin-responsive and ghrelin-unresponsive neurons, respectively, to increase [Ca 2+ ] i . We suggest ARC N- and L-type Ca 2+ channels as potential targets for activating, respectively, ghrelin-responsive, and unresponsive NPY neurons to treat anorexia.

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“…Interestingly, rare human missense or nonsense GHSR variants segregating with short stature or GH deficiency, presumed to be loss-of-function mutations on the basis of their in vitro mechanism of action, were documented (Inoue, et al 2011; Pantel, et al 2009; Pantel, et al 2006; Pugliese-Pires, et al 2011), including the GHSR A204E mutation that specifically alters constitutive activity in vitro . Just recently, a knock-in mice model expressing this mutation showed altered GH release, food intake and glycemic control (Torz, et al 2020), therefore demonstrating that the GHSR A204E disease-causing mutation is related to a partial impairment of GHSR functioning. This kind of genetic defect mirrors the mechanism of the present Ghsr Q343X mutation in rat, documenting enhanced GHSR function both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

TheGhsr^Q343Xallele favors the storage of fat by acting on nutrient partitioning

Marion

Zizzari

Denis

et al. 2020

Preprint

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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 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.

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Metabolic insights from a GHSR-A203E mutant mouse model

Cited by 33 publications

References 59 publications

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Ninjin'yoeito Targets Distinct Ca2+ Channels to Activate Ghrelin-Responsive vs. Unresponsive NPY Neurons in the Arcuate Nucleus

TheGhsr^Q343Xallele favors the storage of fat by acting on nutrient partitioning

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Metabolic insights from a GHSR-A203E mutant mouse model

Cited by 33 publications

References 59 publications

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Ninjin'yoeito Targets Distinct Ca2+ Channels to Activate Ghrelin-Responsive vs. Unresponsive NPY Neurons in the Arcuate Nucleus

TheGhsrQ343Xallele favors the storage of fat by acting on nutrient partitioning

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TheGhsr^Q343Xallele favors the storage of fat by acting on nutrient partitioning