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Absence of Cd36 mutation in the original spontaneously hypertensive rats with insulin resistance

Nature Genetics volume 22, pages 226–228 (1999)Cite this article

The spontaneously hypertensive rat (SHR) is a model of human insulin-resistance syndromes due to the presence of essential hypertension, hyperinsulinaemia, glucose intolerance, hypertriglyceridaemia and visceral obesity1,2,3,4,5. In experimental crosses, quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism in adipocytes5, as well as hypertension6 and hypertriglyceridaemia7, have been mapped to an overlapping region of rat chromosome 4. Upon analysis of SHR strains derived from a colony at the NIH, a deletional mutation in Cd36 (formerly Fat) was proposed as the underlying cause of these chromosome 4 QTLs and the clustering of insulin resistance phenotypes in SHR (ref. 8). Here we show that the Cd36 mutation is absent in the original SHR strains, maintained since their development in Japan9 (SHR/Izm), and question the aetiological relevance of the Cd36 mutation to insulin resistance in SHR.

SHR was established as an animal model of genetic hypertension1 and was sent to the NIH Animal Genetic Resource at the F13 generation. Several strains separated from the NIH colony thereafter and were distributed worldwide (Fig. 1c). The observed discrepancy with respect to Cd36 might therefore result from the occurrence of a de novo mutation or acquisition of a foreign chromosomal fragment during breeding at the NIH. To explore these possibilities, we compared allele distribution patterns of chromosome 4 markers among SHR strains (Fig. 1d). Both the three original (B1, CH, CL) and the NIH-derived SHR strains were shown to share an identical chromosomal haplotype on either side of Cd36, supporting the possibility that the Cd36 mutation was introduced as a de novo mutation.

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Figure 1: Cd36 mRNA, Cd36 genotypes, genealogical relationships and comparison of chromosomal haplotypes.
The alternative text for this image may have been generated using AI.
Figure 2: Comparison of insulin and catecholamine action in adipocytes and in vivo phenotypes.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We thank T. Kashiwa, A. Paku and E. Miyazaki for assistance, and O. Ezaki, A. Hasty and T. Suzuki for advice. This work was supported by the Promotion of Fundamental Studies in Health Science of The Organization for Pharmaceutical Safety and Research (OPPSR) and by Health Sciences Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare of Japan.

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Authors and Affiliations

  1. Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Takanari Gotoda, Yoko Iizuka, Jun-ichi Osuga, Hitoshi Shimano, Shun Ishibashi & Nobuhiro Yamada

  2. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Norihiro Kato

  3. The Wellcome Trust Centre for Human Genetics, Oxford, UK

    Marie-Therese Bihoreau

  4. Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan

    Toru Murakami

  5. Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan

    Yukio Yamori

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  1. Takanari Gotoda
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Correspondence to Takanari Gotoda.

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Gotoda, T., Iizuka, Y., Kato, N. et al. Absence of Cd36 mutation in the original spontaneously hypertensive rats with insulin resistance. Nat Genet 22, 226–228 (1999). https://doi.org/10.1038/10285

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