Neuromedin beta: a strong candidate gene linking eating behaviors and susceptibility to obesity.

BACKGROUND Obesity is frequently associated with eating disorders, and evidence indicates that both conditions are influenced by genetic factors. However, little is known about the genes influencing eating behaviors. OBJECTIVE The objective was to identify genes associated with eating behaviors. DESIGN Three eating behaviors were assessed in 660 adults from the Quebec Family Study with the use of the Three-Factor Eating Questionnaire. A genome-wide scan was conducted with a total of 471 genetic markers spanning the 22 autosomes to identify quantitative trait loci for eating behaviors. Body composition and macronutrient and energy intakes were also measured. RESULTS Four quantitative trait loci were identified for disinhibition and susceptibility to hunger. Of these, the best evidence of linkage was found between a locus on chromosome 15q24-q25 and disinhibition (P <0.0058) and susceptibility to hunger (P <0.0001). After fine-mapping, the peak linkage was found between markers D15S206 and D15S201 surrounding the neuromedin beta (NMB) gene. A missense mutation (p.P73T) located within the NMB gene showed significant associations with eating behaviors and obesity phenotypes. The T73T homozygotes were 2 times as likely to exhibit high levels of disinhibition (odds ratio: 1.8; 95% CI: 1.07, 2.89; P=0.03) and susceptibility to hunger (odds ratio: 1.9; 95% CI: 1.15, 3.06; P=0.01) as were the P73 allele carriers. Six-year follow-up data showed that the amount of body fat gain over time in T73T subjects was >2 times that than in P73P homozygotes (3.6 compared with 1.5 kg; P <0.05). CONCLUSION The results suggest that NMB is a very strong candidate gene of eating behaviors and predisposition to obesity.

[1]  C. Bouchard,et al.  Familial resemblance in eating behaviors in men and women from the Quebec Family Study. , 2005, Obesity research.

[2]  Mohammad A Ghatei,et al.  Inhibition of food intake in obese subjects by peptide YY3-36. , 2003, The New England journal of medicine.

[3]  C. Bouchard,et al.  Long-term adiposity changes are related to a glucocorticoid receptor polymorphism in young females. , 2003, The Journal of clinical endocrinology and metabolism.

[4]  C. Bouchard,et al.  Do 6-y changes in eating behaviors predict changes in body weight? Results from the Québec Family Study , 2003, International Journal of Obesity.

[5]  J. Després,et al.  Eating behaviors and indexes of body composition in men and women from the Québec family study. , 2003, Obesity research.

[6]  P. Sullivan,et al.  Genetic and environmental contributions to obesity and binge eating. , 2003, The International journal of eating disorders.

[7]  T. Ortiga-Carvalho,et al.  The autocrine/paracrine regulation of thyrotropin secretion. , 2003, Thyroid : official journal of the American Thyroid Association.

[8]  Ze-Guang Han,et al.  The gene expression profiling of human visceral adipose tissue and its secretory functions. , 2003, Biochemical and biophysical research communications.

[9]  Braxton D Mitchell,et al.  Eating behavior in the Old Order Amish: heritability analysis and a genome-wide linkage analysis. , 2002, The American journal of clinical nutrition.

[10]  H. Ogura,et al.  Modulation of 5‐HT system in mice with a targeted disruption of neuromedin B receptor , 2002, Journal of neuroscience research.

[11]  M. Charles,et al.  [Prevalence of obesity in adults in France: the situation in 2000 established from the OBEPI Study]. , 2002, Annales d'endocrinologie.

[12]  R. Roubenoff,et al.  Eating behavior correlates of adult weight gain and obesity in healthy women aged 55-65 y. , 2002, The American journal of clinical nutrition.

[13]  R. Leach,et al.  The worldwide obesity epidemic. , 2001, Obesity research.

[14]  M. Simon,et al.  Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Y. Chagnon,et al.  A genome-wide scan for abdominal fat assessed by computed tomography in the Québec Family Study. , 2001, Diabetes.

[16]  R. Elston,et al.  Haseman and Elston revisited: The effects of ascertainment and residual familial correlations on power to detect linkage , 2000, Genetic epidemiology.

[17]  P. Sullivan,et al.  Outcome of anorexia nervosa: eating attitudes, personality, and parental bonding. , 2000, The International journal of eating disorders.

[18]  Y. Chagnon,et al.  Genome-wide search for genes related to the fat-free body mass in the Québec family study. , 2000, Metabolism: clinical and experimental.

[19]  J. Michaud,et al.  ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus , 2000, Mechanisms of Development.

[20]  K. Grzeschik,et al.  Significant association between a silent polymorphism in the neuromedin B gene and body weight in German children and adolescents , 2000, Acta Diabetologica.

[21]  A. Zinn,et al.  Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. , 2000, Human molecular genetics.

[22]  G. Abecasis,et al.  A general test of association for quantitative traits in nuclear families. , 2000, American journal of human genetics.

[23]  M A Province,et al.  The Future of Path Analysis, Segregation Analysis, and Combined Models for Genetic Dissection of Complex Traits , 1999, Human Heredity.

[24]  A. Rissanen,et al.  Environmental factors in the development of obesity in identical twins , 1999, International Journal of Obesity.

[25]  M. Westerterp-Plantenga,et al.  Predictors of weight maintenance. , 1999, Obesity research.

[26]  A. Stunkard,et al.  The Eating Inventory in obese women: Clinical correlates and relationship to weight loss , 1998, International Journal of Obesity.

[27]  R. Wing,et al.  Psychological symptoms in individuals successful at long-term maintenance of weight loss. , 1998, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[28]  M. Westerterp-Plantenga,et al.  Determinants of weight maintenance in women after diet-induced weight reduction , 1998, International Journal of Obesity.

[29]  P. Sullivan,et al.  Food cravings in women with a history of anorexia nervosa. , 1997, The International journal of eating disorders.

[30]  Susan L. Johnson,et al.  Putting the Behavior into the Behavior Genetics of Obesity , 1997, Behavior genetics.

[31]  L. Hoffer,et al.  Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. , 1997, The Journal of clinical endocrinology and metabolism.

[32]  L. Lönn,et al.  Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. , 1997, The Journal of clinical endocrinology and metabolism.

[33]  N. Geary,et al.  Brief, Meal-Contingent Infusions of Gastrin-Releasing Peptide1–27 and Neuromedin B-10 Inhibit Spontaneous Feeding in Rats , 1996, Physiology & Behavior.

[34]  R. Roeder,et al.  Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Pekkarinen,et al.  Two year maintenance of weight loss after a VLCD and behavioural therapy for obesity: correlation to the scores of questionnaires measuring eating behaviour. , 1996, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[36]  C. Bouchard.  Genetic epidemiology, association, and sib-pair linkage: results from the Quebec Family Study , 1996 .

[37]  G. Bray,et al.  Molecular and genetic aspects of obesity , 1996 .

[38]  C. Champagne,et al.  The association of body weight, dietary intake, and energy expenditure with dietary restraint and disinhibition. , 1995, Obesity research.

[39]  T. Adrian,et al.  Bombesin receptor subtype mediation of gastroenteropancreatic hormone secretion in rats , 1994, Peptides.

[40]  M. Sullivan,et al.  Predictors and Effects of Long-term Dieting on Mental Well-being and Weight Loss in Obese Women , 1994, Appetite.

[41]  E. Diaz,et al.  Energy expenditure and everyday eating behavior in healthy young women. , 1991, The American journal of clinical nutrition.

[42]  T. Wadden,et al.  Restrained eating and human obesity. , 2009, Nutrition reviews.

[43]  J. Westenhoefer,et al.  Some restrictions on dietary restraint , 1990, Appetite.

[44]  K. Pirke,et al.  A comparison of the validity of three scales for the assessment of dietary restraint. , 1989, Journal of abnormal psychology.

[45]  S. Johnston,et al.  Specific neuroanatomical and neurochemical correlates of grooming and satiety effects of bombesin , 1988, Peptides.

[46]  S. Johnston,et al.  Specific neuroanatomical and neurochemical correlates of locomotor and grooming effects of bombesin , 1988, Peptides.

[47]  E. Spindel,et al.  Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin. , 1988, The Journal of biological chemistry.

[48]  A. Stunkard,et al.  The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. , 1985, Journal of psychosomatic research.

[49]  C. Bouchard,et al.  The reproducibility of a three-day dietary record , 1983 .

[50]  H. White.  A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test for Heteroskedasticity , 1980 .

[51]  H. L. Le Roy,et al.  Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability; Vol. IV , 1969 .