Genetic deletion of the ghrelin receptor (GHSR) impairs growth and blunts endocrine response to fasting in Ghsr-IRES-Cre mice

Peris-Sampedro, Fiona; Stoltenborg, Iris; May, Marie V. Le; Zigman, Jeffrey M.; Adan, Roger A.H.; Dickson, Suzanne L.

doi:10.1016/j.molmet.2021.101223

Cited by 11 publications

(23 citation statements)

References 42 publications

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“…The ensemble of responses to the cued PB suggest that olfactory food cues engage different pathways involved in motivation, feeding and energy homeostasis. Consistent with this, we found that a 20-min exposure to PB smell activated cells in the Arc in ad libitum-fed rats, similar to that observed for other orexigenic stimuli, such as fasting [37] and ghrelin administration [24]. Notably, the olfactory PB cue did not induce Fos protein expression in any other hypothalamic or reward-linked areas.…”

Section: Discussionsupporting

confidence: 88%

“…Free-floating sections were processed for the immunohistochemical detection of Fos protein using the 3,3′-diaminobenzidine (DAB)-hydrogen peroxidase method [ 24 ]. After deactivation of endogenous peroxidases, the sections were rinsed with 0.1 M PBS + 0.3% Triton X-100 prior to being blocked for 1 h at room temperature in 0.1 M PBS, 3% normal goat serum, 0.25% BSA and 0.3% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

“…Unilateral images (5 sections per rat from 2.04 to 3.72 caudal to bregma) were acquired from rostral to caudal using a DMRB fluorescence microscope (10X/N.A. 0.30; Leica Microsystems, Wetzlar, Germany), as previously described in [ 24 ]. The number of Fos+ cells per section was counted manually in ImageJ/Fiji (NIH, Bethesda, MD, USA) using the Cell counter plug-in.…”

Section: Methodsmentioning

confidence: 99%

“…Candidate Arc cells activated during exposure to the olfactory PB cue included those whose known distribution (based on the Allen Brain Atlas) shows some overlap with the Fos+ cells and that are known to be embedded within the feeding circuits (AgRP, POMC and dopamine) and/or that contain GHSR [ 16 , 25 , 26 ]. Triple fluorescent in situ hybridization using RNAscope ® [ 24 ] was performed to study the potential co-expression of Fos ( c-Fos probed) with GHSR ( Ghsr probed), AgRP ( Agrp probed), POMC ( Pomc probed) and dopamine ( Tyrosine hydroxylase [ Th ] probed) in the Arc of PB taste-familiar rats ( n = 3–4) upon a 20-min exposure to PB odor. To this end, three independent assays were run: (i) c-Fos , Ghsr and Agrp ; (ii) c-Fos , Ghsr and Pomc ; and (iii) c-Fos , Ghsr and Th .…”

Section: Methodsmentioning

confidence: 99%

“…DAPI stain was used for cellular recognition. DAPI-identified cells with >1–3 dots/cell were defined as being positive for a given peptide [ 24 ]. The quantification of the co-expression per hemisection was averaged for each brain and, ultimately, for each experimental group.…”

Section: Methodsmentioning

confidence: 99%

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The Orexigenic Force of Olfactory Palatable Food Cues in Rats

et al. 2021

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Environmental cues recalling palatable foods motivate eating beyond metabolic need, yet the timing of this response and whether it can develop towards a less palatable but readily available food remain elusive. Increasing evidence indicates that external stimuli in the olfactory modality communicate with the major hub in the feeding neurocircuitry, namely the hypothalamic arcuate nucleus (Arc), but the neural substrates involved have been only partially uncovered. By means of a home-cage hidden palatable food paradigm, aiming to mimic ubiquitous exposure to olfactory food cues in Western societies, we investigated whether the latter could drive the overeating of plain chow in non-food-deprived male rats and explored the neural mechanisms involved, including the possible engagement of the orexigenic ghrelin system. The olfactory detection of a familiar, palatable food impacted upon meal patterns, by increasing meal frequency, to cause the persistent overconsumption of chow. In line with the orexigenic response observed, sensing the palatable food in the environment stimulated food-seeking and risk-taking behavior, which are intrinsic components of food acquisition, and caused active ghrelin release. Our results suggest that olfactory food cues recruited intermingled populations of cells embedded within the feeding circuitry within the Arc, including, notably, those containing the ghrelin receptor. These data demonstrate the leverage of ubiquitous food cues, not only for palatable food searching, but also to powerfully drive food consumption in ways that resonate with heightened hunger, for which the orexigenic ghrelin system is implicated.

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The Orexigenic Force of Olfactory Palatable Food Cues in Rats

et al. 2021

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Molecular and cellular mechanisms underlying the hepatoprotective role of ghrelin against NAFLD progression

et al. 2022

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LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

Shankar

Metzger

Singh

et al. 2021

Molecular Metabolism

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Objective The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. Methods We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. Results LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2–119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O 2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. Conclusions LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion...

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Genetic deletion of the ghrelin receptor (GHSR) impairs growth and blunts endocrine response to fasting in Ghsr-IRES-Cre mice

Cited by 11 publications

References 42 publications

The Orexigenic Force of Olfactory Palatable Food Cues in Rats

The Orexigenic Force of Olfactory Palatable Food Cues in Rats

Molecular and cellular mechanisms underlying the hepatoprotective role of ghrelin against NAFLD progression

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

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