Abstract
Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional in vitro characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.
Highlights
The G protein coupled receptor (GPCR) trace amine associated receptor 1 (TAAR1) is activated by biogenic trace amines such as beta-phenylethyl amine (PEA) and tyramine or octopamine (Borowsky et al, 2001; Lindemann and Hoener, 2005)
Screening of 314 patients with impaired glucose tolerance revealed three heterozygous carriers of single nucleotide variants in the trace amine-associated receptor 1 (TAAR1) coding region: p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ile171Leu (I171L, rs200795344). This corresponds to a minor allele frequency (MAF) of 0.16% for each variant in this patient sample
Identified TAAR1 Variants Are Properly Expressed at the Cell Surface
Summary
The G protein coupled receptor (GPCR) trace amine associated receptor 1 (TAAR1) is activated by biogenic trace amines such as beta-phenylethyl amine (PEA) and tyramine or octopamine (Borowsky et al, 2001; Lindemann and Hoener, 2005). In pancreatic beta-cells, TAAR1 activation by T1AM enhances insulin secretion (Regard et al, 2007). Insulin secretion from a pancreatic beta-cell line and human pancreatic islets could be stimulated under high glucose concentrations (Raab et al, 2016) and treatment of diet-induced obese mice with RO5166017 resulted in reduction of food intake and body weight (Raab et al, 2016). TAAR1 was found to be highly expressed in pancreatic islets (Regard et al, 2007; Raab et al, 2016), the stomach, and gut (Ito et al, 2009; Revel et al, 2013; Raab et al, 2016)
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