G protein-coupled receptor 12 deficiency results in dyslipidemia and obesity in mice

https://doi.org/10.1016/j.bbrc.2006.07.090Get rights and content

Abstract

Obesity has been proposed to be a result of an imbalance in the physiological system that controls and maintains the body energy homeostasis. Several G-protein coupled receptors (GPCRs) are involved in the regulation of energy homeostasis. To investigate the importance of GPCR12, mice deficient of this receptor (GPCR12 KO) were studied regarding metabolism. Expression of GPCR12 was found primarily in the limbic and sensory systems, indicating its possible involvement in motivation, emotion together with various autonomic functions, and sensory information processing. GPCR12 KO mice were found to have higher body weight, body fat mass, lower respiratory exchange ratio (RER), hepatic steatosis, and were dyslipidemic. Neither food intake nor energy in faeces was affected in the GPCR12 KO mice. However, lower energy expenditure was found in the GPCR12 KO mice, which may explain the obesity. In conclusion, GPCR12 is considered important for the energy balance since GPCR12 KO mice develop obesity and have lower energy expenditure. This may be important for future drugs that target this receptor.

Section snippets

Materials and methods

Generation and maintenance of the GPCR12 knockout mice. Heterozygous GPCR12 knockout mice (GPCR+/−) were obtained from Deltagen (San Carlos, CA, USA). A schematic diagram of the mouse GPCR12 gene, including the disrupted region, is outlined in Fig. 1. The GPCR12 gene was targeted by homologous recombination in ES cells derived from 129/OlaHsd mouse substrain and injected into blastocysts. Mice carrying a disrupted GPCR12 gene were generated by breeding the chimeric mice with C57BL/6 females.

Generation of the GPCR12 KO mice

GPCR12 KO mice were generated by targeted deletion of a 353-bp segment of the coding region in exon 2 (Fig. 1). This region corresponds to nucleotides 155–507 of the mRNA. Genotyping of chimeric mice and subsequent progeny was performed by PCR and confirmed by Southern blot analysis (data not shown). The genomic region deleted by the targeting vector was replaced by a Lac Z-Neo reporter cassette that could be used to analyse GPCR12 expression in vivo. The ratio of offspring genotypes did not

Discussion

In this study, mice having a disruption in the G protein-coupled receptor 12 gene (GPCR12 KO) were studied to investigate the importance of GPCR12 in metabolism. This is the first study of this mouse line reported in the literature. We found that GPCR12 deficiency resulted in obesity and dyslipidemia. The increased body weight and obesity may be explained by a decrease in energy expenditure since GPCR12 KO mice had unaltered food intake, locomotor activity, body temperature, and faeces energy

Acknowledgments

Lena Amrot Fors, Anna Tuneld, Charlotte Lindgren, Anne-Cristine Carlsson, Martina Johansson, Gisela Häggblad, and Marie-Louise Berglund Zackrisson who kindly helped with the serum assays. Also, we thank Magnus Kjaer for invaluable help with statistical analysis.

References (29)

  • M.D. Thompson et al.

    The G protein-coupled receptors: pharmacogenetics and disease

    Crit. Rev. Clin. Lab. Sci.

    (2005)
  • A. Ignatov et al.

    Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development

    J. Neurosci.

    (2003)
  • M. Bohlooly-Y et al.

    Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia

    Diabetes

    (2005)
  • E. Egecioglu et al.

    Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice

    Am. J Physiol.—Endocrinol. Metab.

    (2006)
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