Abstract
G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments.
Highlights
With the availability of large public data sets, the knowledge of many mammalian genomic sequences, and large-scale genotyping resources, numerous loci which have potentially been under selection in the entire human species, or locally in specific human populations have been identified [1,2,3,4,5,6,7]
GPR34 and GPR82 belong to the group of P2Y12-like receptors, all structurally related to the clopidogrel-sensitive ADP receptor P2Y12 [10,11]
Because the functional relevance of calmodulin-dependent serine protein kinase (CASK) and GPR34 has recently been evaluated but not the one of GPR82, we studied this orphan G proteincoupled receptors (GPCR) in more detail
Summary
With the availability of large public data sets, the knowledge of many mammalian genomic sequences, and large-scale genotyping resources, numerous loci which have potentially been under selection in the entire human species, or locally in specific human populations have been identified [1,2,3,4,5,6,7]. Meta-analysis of genomic scans for signatures of selection revealed a number of such loci containing GPCR genes [9]. The X-chromosomal Ca2+/calmodulin-dependent serine protein kinase (CASK) locus which contains two orphan rhodopsin-like GPCR, GPR34 and GPR82, is one of these genomic regions and displays significant signatures of recent selection in human populations [6]. Several members of the P2Y12-like receptor group have been assigned to nucleotide derivates and lipids as physiological ligands [13,14,15] among them GPR34 as receptor for lysophosphatidylserine (lyso-PS), a finding that is still under discussion [16]. The link between both, the potential selection of the genomic locus containing GPR34 and GPR82 and the physiological relevance of the two GPCR is still unknown
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