Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats

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Abstract

The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat , as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.

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Figure 1: Defective insulin and catecholamine action in SHR adipocytes and correction of the defect in chromosome 4 congenic rats.
Figure 2: cDNA microarray analysis of gene expression in SHR adipose tissue.
Figure 3: Radiation hybrid mapping of Cd36 to rat chromosome 4.
Figure 4: SHR Cd36 cDNA contains an aberrant 3´ tail and multiple coding sequence variants.
Figure 5: Distribution of amino acid changes and silent polymorphisms in SHR Cd36.
Figure 6: Complete sequence divergence in the 3' untranslated tail of SHR and WKY Cd36 cDNA.
Figure 7: Location of Cd36 on chromosome 4 determined by linkage analysis using a HinfI RFLP in the Cd36 cDNA sequence and genomic characterization by Southern blot.
Figure 8: Analysis of Cd36 transcripts and protein products.

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Acknowledgements

This work was carried out under intramural funding from the MRC Clinical Sciences Centre. We acknowledge support from the British Heart Foundation (grant no. PG/95185 and PG/98022) and the European Community Concerted Action on Blood Pressure to T.J.A.; NIH grant RO1 HL56028 to T.W.K.; grant 204/98/K015 from the Grant Agency of the Czech Republic to M.P.; and NIH grant DK33301 and the Sumitomo Chemical Company to N.A.A. M.P. is an International Scholar of the Howard Hughes Medical Institute. J.S. was supported by a Bristol Myers Squibb Award for Cardiovascular Research.

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Correspondence to Timothy J. Aitman.

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Aitman, T., Glazier, A., Wallace, C. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet 21, 76–83 (1999) doi:10.1038/5013

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