The beta3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64.
The beta3-adrenergic receptor (ADRbeta3) is a seven-membrane spanning, G-protein linked receptor expressed in brown adipose tissue in rodents, and visceral adipose tissue in humans. Stimulation of the receptor by norepinephrine leads to lipolysis and thermogenesis. In rodent models of obesity and diabetes, administration of beta3-agonists results in weight loss and improved glucose tolerance. Studies indicate that the pharmacological properties of the ADRbeta3 differ markedly between rodents and humans, making generalizations of rodent studies to humans difficult. We hypothesized that the obesity and diabetes prone rhesus monkey (Macaca mulatta) would provide an excellent animal model to study the role of the ADRbeta3 in the development of obesity and diabetes as well as for assessment of the therapeutic efficacy of beta3-agonists. We sequenced the entire coding region of the rhesus ADRbeta3 gene. Like humans, the rhesus ADRbeta3 has two exons. There is 89% amino acid (aa) identity between human and rhesus compared to 82% aa identity between human and mouse. A single base deletion results in divergence of the intracellular carboxy terminus accounting for 26 of the 45 aa changes and 10 additional aa. Of the 15 rhesus monkeys studied, all were homozygous for Arg64. In humans, Arg64 (rather than Trp) is associated with increased body mass index, insulin resistance, and an earlier onset of type II diabetes mellitus. We conclude that the rhesus ADRbeta3 is more similar to the human ADRbeta3 than to the rodent ADRbeta3 suggesting that this primate model may be more appropriate for physiologic and therapeutic studies of the ADRbeta3 axis, and that Arg64 may influence susceptibility in this species to obesity, insulin resistance, and type II diabetes.
Walston
J
J
Division of Geriatric Medicine and Gerontology, Johns Hopkins University Bayview Medical Center, Baltimore, MD 21224, USA. jwalston@welchlink.welch.jhu.edu
Lowe
A
A
Silver
K
K
Yang
Y
Y
Bodkin
N L
NL
Hansen
B C
BC
Shuldiner
A R
AR
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D003062:Codon; D003596:Cytosine; D004247:DNA; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D022702:Receptors, Adrenergic, beta-3
D003062:Codon; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D003596:Cytosine; D004247:DNA; D001120:Arginine