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Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats

Nature Genetics volume 16, pages 197–201 (1997)Cite this article

Abstract

Coronary heart disease, hypertension, non-insulin-dependent diabetes and obesity are major causes of ill health in industrial societies. Disturbances of carbohydrate and lipid metabolism are a common feature of these disorders1–9. The bases for these disturbances and their roles in disease pathogenesis are poorly understood. The spontaneously hypertensive rat (SHR), a widely used animal model of essential hypertension10, has a global defect in insulin action on glucose metabolism and shows reduced catecholamine action on lipolysis in fat cells11–14. In our study we used cellular defects in carbohydrate and lipid metabolism to dissect the genetics of defective insulin and catecholamine action in the SHR strain. In a genome screen for loci linked to insulin and catecholamine action, we identified two quantitative trait loci (QTLs) for defective insulin action, on chromosomes 4 and 12. We found that the major (and perhaps only) genetic determinant of defective control of lipolysis in SHR maps to the same region of chromosome 4. These linkage results were ascertained in at least two independent crosses. As the SHR strain manifests many of the defining features of human metabolic Syndrome X, in which hypertension associates with insulin resistance, dyslipidaemia and abdominal obesity, the identification of genes for defective insulin and catecholamine action in SHR may facilitate gene identification in this syndrome and in related human conditions, such as type-2 diabetes and familial combined hyperlipidaemia.

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Authors and Affiliations

  1. Molecular Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, London, W12 ONN, UK

    Timothy J. Aitman, Takanari Gotoda, Alison L. Evans, Helen Imrie, Karen E. Heath, Paul M. Trembling, Hazel Truman, Caroline A. Wallace, Ahmadur Rahman & James Scott

  2. Departments of Medicine Royal Postgraduate Medical School, Hammersmith Hospital, London, W12 ONN, UK

    Timothy J. Aitman, Paul M. Trembling & James Scott

  3. Departments of Medical Statistics and Evaluation, Royal Postgraduate Medical School, Hammersmith Hospital, London, W12 ONN, UK

    Caroline Doré

  4. Institute of Molecular Medicine, Oxford, OX3 9DU, UK

    Jonathan Flint

  5. Department of Biology, 1st Medical Faculty, Charles University, 12800, Prague, 2, Czech Republic

    Vladimir Kren & Michal Pravenec

  6. Institute of Physiology, Czech Academy of Sciences, 14220, Prague, 4, Czech Republic

    Vladimir Kren, Vaclav Zidek & Michal Pravenec

  7. Department of Laboratory Medicine, University of California, San Francisco, California, 94143, USA

    Theodore W. Kurtz

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  1. Timothy J. Aitman
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Correspondence to Timothy J. Aitman.

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Aitman, T., Gotoda, T., Evans, A. et al. Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats. Nat Genet 16, 197–201 (1997). https://doi.org/10.1038/ng0697-197

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