A Variation in the Ghrelin Gene Increases Weight and Decreases Insulin Secretion in Tall, Obese Children

Abstract

Ghrelin is a recently recognized gut-brain peptide originally derived from the gastric mucosa. It stimulates growth hormone release, increases appetite and facilitates fat storage, and may interact with glucose metabolism. We studied the ghrelin gene in a group of 70 tall and obese children (mean age 9.4 year, Z body mass index [BMI] and Z height >3 and/or BMI percentile >99%). We found 10 single nucleotide polymorphisms. One common polymorphism of the ghrelin gene, which corresponds to an amino acid change in the tail of the prepro-ghrelin molecule, was significantly associated with children with a higher BMI (P = 0.001), and with lower insulin secretion during the first part of an oral glucose tolerance test (P = 0.05) although no difference in glucose levels was noted. This might suggest increased insulin sensitivity, although this is not supported by the lack of difference in fasting and 2 hour insulin levels; alternatively, this may be indicative of impaired first phase insulin secretion. These data suggest that variations in the ghrelin gene contribute to obesity in children and may modulate glucose-induced insulin secretion.

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity and age of onset

“…Met72GHREL carriers in the general population display the lowest BMI and the lowest fat mass ; with less visceral fat and a lower fasting respiratory quotient, indicating a greater utilization of fat as an energy substrate (Ukkola et al, 2002). The Leu72Met substitution is also associated with an earlier age at onset of anorexia nervosa, as previously reported in obese subjects (Ukkola et al, 2001;Korbonits et al, 2002;Miraglia del Giudice et al, 2004).…”

Ghrelin in obesity and endocrine diseases

“…Relationships have been described between obesity and genomic variants of the ghrelin (GHRL) (Gueorguiev et al, 2009;Korbonits et al, 2002;Kuzuya et al, 2006;Leskela et al, 2009;Miraglia Del et al, 2004;Ukkola et al, 2001;Ukkola et al, 2002) M a n u s c r i p t 12 and ghrelin receptor (GHS-R) (Baessler et al, 2005;Gueorguiev et al, 2009;Liu et al, 2007) genes.…”

Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort

“…The Leu72Met polymorphism of preproghrelin was previously found in a group of obese French children and adolescents. 9 In this case, a significant association was observed between the 72Met allele and earlier age of onset of obesity. Additionally, obese Italian children and adolescents with the preproghrelin 72Met allele have also been reported to become obese earlier than homozygous patients for the wild Leu72 allele, even though 72Met allelic frequency was similar between obese and control groups.…”

“…5,6 Recently, three major polymorphisms in the human ghrelin gene were described. 7 One of these nucleotide changes, a single-base substitution C214A with Met replacing Leu at codon 72 in the preproghrelin amino-acid sequence, seems to be associated with an earlier onset of obesity, [7][8][9] but it has also been proposed that 72Met could provide protection against the accumulation of fat. 10 Thus, previous studies on preproghrelin genetic variants have arrived at contradictory findings as to their role in obesity.…”