Reduced intake of carbohydrate prevents the development of obesity and impaired glucose metabolism in ghrelin O-acyltransferase knockout mice

Kouno, Tetsuya; Akiyama, Nobuteru; Fujieda, Kumiko; Nanchi, Isamu; Okuda, Tomohiko; Iwasaki, Takanori; Oka, Shogo; Yukioka, Hidekazu

doi:10.1016/j.peptides.2016.11.003

Cited by 20 publications

(17 citation statements)

References 16 publications

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“…Acyl-ghrelin administration shifts the food preference toward fat-rich diets and leads to increased consumption of palatable saccharin solution 64 . Ghrelin-null and GOAT-null mice are indistinguishable from wild-type mice when fed normal chow 55 , however, they are protected from DIO 65 and display reduced hedonic feeding.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Monteiro

Batterham

2017

Gastroenterology

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The gastrointestinal (GI) tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural and nutrient signals emanating from the GI tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacological and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing bodyweight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy. However, the recent finding of sustained weight-reduction in response to systemic administration of a long-acting analog of the gut-hormone glucagon-like peptide-1 (GLP-1) highlights the therapeutic potential of gut-derived signals acting via non-physiological mechanisms. Thus, we also review therapeutics strategies being utilized or developed to leverage GI signals in order to treat obesity.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Monteiro

Batterham

2017

Gastroenterology

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“…O -acyltransferase (GOAT) transfers an acyl group from the fatty acids to the serine-3 residue of ghrelin and, thus, stimulates GH secretion and food intake [ 4 , 5 ]. GOAT activates ghrelin depending on an esterification reaction, and blockade of GOAT activity induces less food intake and weight gain [ 4 , 6 ]. Therefore, GOAT may offer a therapeutic target for obesity.…”

Section: Introductionmentioning

confidence: 99%

Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism

Liang

Wang

et al. 2018

Bioscience Reports

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Ghrelin, an acylated peptide hormone of 28 amino acids, is an endogenous ligand of the released growth hormone secretagogue receptor (GHSR). Ghrelin has been isolated from human and rat stomach and is also detected in the hypothalamic arcuate nucleus. Ghrelin receptor is primarily located in the neuropeptide Y and agouti-related protein neurons. Many previous studies have shown that ghrelin and GHSR are involved in the regulation of energy homeostasis, and its administration can increase food intake and body weight gain. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acid level. Ghrelin appears to modulate the response to food cues via a neural network involved in the regulation of feeding and in the appetitive response to food cues. It also increases the response of brain areas involved in visual processing, attention, and memory to food pictures. Ghrelin is also an important factor linking the central nervous system with peripheral tissues that regulate lipid metabolism. It promotes adiposity by the activation of hypothalamic orexigenic neurons and stimulates the expression of fat storage-related proteins in adipocytes. Meanwhile, ghrelin exerts direct peripheral effects on lipid metabolism, including increase in white adipose tissue mass, stimulation of lipogenesis in the liver, and taste sensitivity modulation.

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“…In recent years, transgenic mouse lines with mutations in the ghrelin system have been developed. Ghrelin peptide, GHSR and GOAT knockout (KO) mice are available, and these models have been substantially studied in terms of appetite, food intake, energy expenditure, metabolism, and reward processing ( 21 – 26 ). Ghrelin peptide-deficient mice, however, display limited physiological and behavioral modifications compared with wild type, with no differences in body weight, body composition, or food consumption ( 23 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model

et al. 2018

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Background/objectivesGhrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts through binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification and initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing.MethodsUsing CRISPR/Cas9, we developed a GHSR knockout (KO) in a Wistar background. Loss of GHSR mRNA expression was histologically verified using RNAscope in wild-type WT (n = 2) and KO (n = 2) rats. We tested the effects of intraperitoneal acyl-ghrelin administration on food consumption and plasma growth hormone (GH) concentrations in WT (n = 8) and KO (n = 8) rats. We also analyzed locomotion, food consumption, and body fat composition in these animals. Body weight was monitored from early development to adulthood.ResultsThe RNAscope analysis revealed an abundance of GHSR mRNA expression in the hypothalamus, midbrain, and hippocampus in WTs, and no observed probe binding in KOs. Ghrelin administration increased plasma GH levels (p = 0.0067) and food consumption (p = 0.0448) in WT rats but not KOs. KO rats consumed less food overall at basal conditions and weighed significantly less compared with WTs throughout development (p = 0.0001). Compared with WTs, KOs presented higher concentrations of brown adipose tissue (BAT) (p = 0.0322).ConclusionsWe have verified GHSR deletion in our KO model using histological, physiological, neuroendocrinological and behavioral measures. Our findings indicate that GHSR deletion in rats is not only associated with a lack of response to ghrelin, but also associated with decreases in daily food consumption and body growth, and increases in BAT. This GHSR KO Wistar rat model provides a novel tool for studying the role of the ghrelin system in obesity and in a wide range of medical and neuropsychiatric disorders.

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Reduced intake of carbohydrate prevents the development of obesity and impaired glucose metabolism in ghrelin O-acyltransferase knockout mice

Cited by 20 publications

References 16 publications

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model

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