The β 3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64

• Published in: Gene Vol. 188; no. 2; pp. 207 - 213
• Main Authors: Walston, Jeremy, Lowe, Adam, Silver, Kristi, Yang, Yufeng, Bodkin, Noni L, Hansen, Barbara C, Shuldiner, Alan R
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 1997
• Subjects: amino acid sequences; arginine; biological resistance; Brown adipose tissue; codons; deletions; diabetes mellitus; exons; genbank/u63591; genbank/u63592; humans; insulin; Insulin resistance syndrome; introns; Macaca mulatta; molecular sequence data; Non-insulin dependent diabetes mellitus; norepinephrine; nucleotide sequences; obesity; receptors; resistance; species differences; structural genes; Sympathetic nervous system; Visceral fat; aa, amino acid(s); C, cytosine; kb, kilobase(s) or 1000 bp; Brown adipose tissue; bp, base pair(s); RT, reverse transcription; A, adenosine; c-term, carboxy-terminal end; ECL, extracellular loop; G, guanine; RFLP, restriction fragment length polymorphism; ADRβ 3, β 3-adrenergic receptor; βARK, β-adrenergic receptor kinase; TAE buffer, Tris-acetate-EDTA buffer; Non-insulin dependent diabetes mellitus; T, thymidine; cAMP, cyclic adenosine 3′,5′-monophosphate; TMD, transmembrane domain; Visceral fat; PE/ABD, Perkin-Elmer/Applied Biosystems; Sympathetic nervous system; ICL, intracellular loop; nt, nucleotide(s); Insulin resistance syndrome; PCR, polymerase chain reaction; PKA, protein kinase A; n-term, amino-terminal end
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/S0378-1119(96)00796-2

The β 3-adrenergic receptor (ADRβ 3) 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 β 3-agonists results in weight loss and improved glucose tolerance. Studies indicate that the pharmacological properties of the ADRβ 3 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 ADRβ 3 in the development of obesity and diabetes as well as for assessment of the therapeutic efficacy of β 3-agonists. We sequenced the entire coding region of the rhesus ADRβ 3 gene. Like humans, the rhesus ADRβ 3 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 Arg 64. In humans, Arg 64 (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 ADRβ 3 is more similar to the human ADRβ 3 than to the rodent ADRβ 3 suggesting that this primate model may be more appropriate for physiologic and therapeutic studies of the ADRβ 3 axis, and that Arg 64 may influence susceptibility in this species to obesity, insulin resistance, and type II diabetes.