A polymorphism in the human agouti-related protein is associated with late-onset obesity.
The mouse agouti-related protein (AGRP) is a powerful appetite effector that results in hyperphagia and the development of obesity when administered intracerebroventricularly or when overexpressed in transgenic mice. Animal studies have also shown that exogenous administration of AGRP predisposes toward hedonic intake of high fat and high sucrose diets. The human ortholog (hAGRP) maps on chromosome 16q22 and has similar physiological properties, as tested in animal models. A polymorphism was identified in the third exon of hAGRP, c.199G-->A, that resulted in a nonconservative amino acid substitution, Ala(67)Thr. Computational analysis of the protein showed significant differences in the coils of the two polymorphic isoforms of the protein. Human studies showed no genotype effects in individuals with a mean age of 25 yr. However, the G/G genotype was significantly associated with fatness and abdominal adiposity in the parental population with a mean age of 53 yr. The c.199G-->A polymorphism in hAGRP could, therefore, play a role in the development of human obesity in an age-dependent fashion.
Argyropoulos
George
G
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA. argyrog@pbrc.edu
Rankinen
Tuomo
T
Neufeld
Doni R
DR
Rice
Treva
T
Province
Michael A
MA
Leon
Arthur S
AS
Skinner
James S
JS
Wilmore
Jack H
JH
Rao
D C
DC
Bouchard
Claude
C
D000225:Adenine; D000328:Adult; D017668:Age of Onset; D054369:Agouti-Related Protein; D000818:Animals; D005091:Exons; D005260:Female; D005838:Genotype; D006147:Guanine; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
C515198:AGRP protein, human; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D006147:Guanine; D000225:Adenine