Research reportPreproghrelin gene polymorphisms in obese Japanese women. Minor homozygotes are light eaters, do not prefer protein or fat, and apparently have a poor appetite☆
Highlights
► We study the correlation between ghrelin gene SNPs and appetite in 117 obese Japanese women. ► Diet Questionnaire showed total food, mineral, sugar, and dairy product intake were low in +3056C/C women. ► Energy balance calculation showed much reduced fat and protein consumption in +3056C/C women. ► −1062C/C women showed low scores for “motivation for eating” and “eating because of stress or something else”. ► Minor homozygotes for ghrelin gene SNPs were light eaters, and had a poor appetite, although they were predisposed to obesity.
Introduction
Ghrelin (GHRL) is a stomach-secreted peptide hormone that stimulates appetite via the hypothalamus, and actively participates in the release of growth hormone (GH), adipogenesis, gut motility, glucose metabolism, and other functions (Chen et al., 2009, Kojima and Kangawa, 2005, Pulkkinen et al., 2010).
The GH-stimulating effect of peripheral acyl ghrelin has been reported to occur through direct central mechanisms. On the other hand, the appetite-stimulating effects can occur via indirect mechanisms such as those involving the vagus nerve in humans (le Roux et al., 2005). Indeed, a ghrelin receptor, type 1a GH secretagogue receptor (GHS-R1a), is localized in many human organs, including the heart, lung, liver, kidney, pancreas, stomach, small and large intestines, adipose tissue, and immune cells, although expressed predominantly in the pituitary, adrenal gland, and spinal cord (Sun et al., 2007, Ueberberg et al., 2009).
In the brain, GHS-R1a mRNA is also detected in the regions other than the hypothalamus and pituitary, such as the ventral tegmental area (VTA) and hippocampus. Functional magnetic resonance imaging (fMRI) revealed that after ghrelin infusion in healthy volunteers, the cerebral response to food pictures was increased in the amygdala, orbitofrontal cortex (OFC), anterior insula, and striatum (Malik, McGlone, Bedrossian, & Dagher, 2008). These regions are part of the mesolimbic reward system and can trigger “hedonic” eating by visual or olfactory food cues. It has been suggested that appetite is separated into two components, homeostatic and hedonic, and that ghrelin primarily controls homeostatic eating modulated in the hypothalamus. As mentioned above, fMRI showed that ghrelin also drives hedonic eating via these regions.
Cummings et al. (2001) reported that plasma ghrelin levels oscillate in humans. They are the lowest shortly after a meal and then rise during the fasting just prior to the next meal, suggesting that ghrelin regulates appetite as a hunger signal. With a highly specific acyl ghrelin assay, Liu et al. (2008) corroborated these oscillations in the fed state. However, under conditions of prolonged fasting, plasma acyl ghrelin concentrations were consistently at the basal level. They also proved that total ghrelin (acyl plus des-acyl) levels remain unchanged, suggesting that acylation of ghrelin by ghrelin O-acyltransferase (GOAT) may be regulated independently of secretion. Kirchner et al. (2009) confirmed that gastric GOAT mRNA levels – as well as preproghrelin levels – decrease significantly on prolonged fasting. They also showed that octanoic acid in gastric dietary lipid was directly used for ghrelin acylation in wild-type mouse, suggesting that the GOAT–ghrelin system acts as a nutrient sensor, which signals the brain to optimally metabolize and store the energy of the ingested lipid.
Relationships between preproghrelin gene single-nucleotide polymorphisms (SNPs) and susceptibility to metabolic syndrome have been intensively investigated. We have also reported the effect of preproghrelin gene SNPs on diabetes and obesity (Takezawa, Yamada, Morita, Aiba, & Watanabe, 2009). We recruited 235 subjects (both men and women) with a BMI > 28.3; conducted the genotyping of above five SNPs in the preproghrelin gene, and studied the association between these SNPs and clinical parameters related to diabetes mellitus or metabolic syndrome. We observed that among obese men, +3056C/C minor homozygotes were susceptible to diabetes mellitus, which was not accompanied by insulin or leptin accumulation. In contrast, in obese women, preproghrelin gene SNPs were suggested to contribute to the development of obesity via aberrant fat storage; minor homozygotes for −1500C/G, −1062G/C, and −994C/T had high BMI and a tendency of fat mass accumulation, particularly that of visceral fat mass, and minor homozygotes for Leu72Met and +3056T/C had reduced serum cholesterol levels and increased visceral adiposity (Takezawa et al., 2009).
In this study, to clarify the relationships between the function of ghrelin, appetite, and susceptibility to metabolic syndrome, with preproghrelin gene SNPs as a clue, we investigated the eating behavior of women who were minor homozygotes for preproghrelin gene SNPs.
Dietary tendency was assessed using a self-administered diet history questionnaire (DHQ) designed by Sasaki, Yanagibori, and Amano (1998) for use in health education in Japan. This questionnaire inquires about the frequency of each food item ingested in the previous month, and the participants’ dietary habits are semi-quantitatively measured from the results. DHQ has been validated by comparison with a 3-day diet record in middle-aged women; it provided a close estimation of nutrients compared with the 3-day diet record (Sasaki et al., 1998).
Dietary habits were investigated using SQEBe (see Guideline for the treatment of obesity, Japan Society for the Study of Obesity., 2006). Eating behavior characteristics more common among overweight patients were extracted from their conversation and compiled into this questionnaire by a physician who was treating obesity (Sakata, 2010, Yoshimatsu, 2009). His aim was to point out recognition gaps between these and non-obese people. It is, however, advantageous since the cause of obesity can be studied from multiple angles.
Section snippets
Subjects
Obese Japanese women aged 40–64 years with a BMI > 28.3 were selected from examinees undergoing a medical checkup at Saku Central Hospital, Nagano, Japan. They were asked to participate in the intervention program for weight loss named the Saku Control Obesity Program (SCOP) (Morita et al., 2008, Watanabe et al., 2007). The women underwent anthropometric and clinical examinations and were assessed for present illness, physical activity, and dietary habits at the start of the program, and we found
Results and discussion
Minor homozygotes for −1062G > C, i.e. −1062C/C women, had lower levels of food group intake than major homozygotes or heterozygotes (Table 1, left). Protein, mineral (calcium, phosphorus, and zinc), and dairy product intake were significantly lower than heterozygotes. Fat intake also tended to be low. The average values of total food intake and energy, carbohydrate, and sugar intake were low, although not significant.
In +3056C/C women, total food intake, mineral, sugar, and dairy product intake
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2023, Journal of King Saud University - ScienceCitation Excerpt :12 SNPs have been found in the GHRL gene, although their functional ramifications have not yet been fully understood (Llamas-Covarrubias et al., 2017). Previous studies have been carried out in obesity with the global population (Martin et al., 2008; Giudice et al., 2004; Gueorguiev et al., 2009; Ukkola et al., 2002; Bai et al., 2021; Gjesing et al., 2010; Leskelä et al., 2009; Takezawa et al., 2013; Takezawa et al., 2009; Zhu et al., 2010). The SNPs of GHRL gene is studies in various human diseases including meta-analysis studies in type 2 diabetes (Huang et al., 2018), gestational diabetes (Madkour et al., 2022), HTN (Berthold et al., 2010; Mager et al., 2006), metabolic syndrome (Mora et al., 2015), NAFLD (Tabaeian et al., 2021), eating disorder (Monteleone et al., 2007; Manfredi et al., 2021) and many other human diseases.
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2020, BoneCitation Excerpt :Furthermore, the ghrelin gene sequence harbors a large number of allele SNPs that may affect plasma levels. For our study, we selected rs27647, rs696217, rs2075356, and rs3755777, which have been indicated to be associated with ghrelin levels, as previously studied for genotypic analysis [35–37]. The results showed no significant differences in the selected SNPs between the AIS and control groups.
Genetic regulation of energy homeostasis
2019, Principles of Nutrigenetics and Nutrigenomics: Fundamentals of Individualized NutritionInteraction between genes involved in energy intake regulation and diet in obesity
2019, NutritionCitation Excerpt :Those with risk allele +3056 T> C (rs2075356 – intron 2) had lower intake of food, dairy products, sugar and calcium, phosphorus, zinc, and magnesium. Additionally, this latter polymorphism also showed a higher preference for carbohydrate intake compared with fats and proteins [52] (Table 1). The leptin hormone is an adiponectin produced mainly by the adipose tissue and encoded by the leptin gene (LEP) that is on chromosome 7 q31.1 [53,54].
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Acknowledgments: We are thankful to Dr. Masahiro Morioka and Dr. Kijo Deura (Saku Central Hospital) for their kind cooperation. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare, Japan, and by research budgets from the Foundation for Total Health Promotion and the Kao Foundation.
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Present address.