Nature Genetics
21, 76 - 83 (1999)
doi:10.1038/5013
Identification of Cd36 (Fat) as an insulin-resistance gene
causing defective fatty acid and glucose metabolism in hypertensive ratsTimothy J. Aitman1, 2, Anne M. Glazier1, Caroline A. Wallace1, Lisa D. Cooper1, Penny J. Norsworthy1, 2, Faisal N. Wahid1, Khulood M. Al-Majali1, Paul M. Trembling1, 2, Christopher J. Mann1, Carol C. Shoulders1, Daniel Graf1, Elizabeth St. Lezin3, Theodore W. Kurtz3, Vladimir Kren4, 5, Michal Pravenec4, 5, Azeddine Ibrahimi6, Nada A. Abumrad6, Lawrence W. Stanton7
& James Scott1, 21
Molecular Medicine Group, MRC Clinical Sciences Centre,
Imperial College School of Medicine, Hammersmith Hospital, London
W12 0NN, UK. 2
Division of National Heart and Lung Institute, Imperial
College School of Medicine, Hammersmith Hospital, London
W12 0NN, UK
3
Department of Laboratory Medicine, University of California
, San Francisco, California 94143,
USA. 4
Department of Biology, 1st Medical Faculty, Charles
University, 12800 Prague 2, Czech Academy of Sciences 14220
Prague 4, Czech Republic. 5
Institute of Physiology, Czech Academy of Sciences
14220 Prague 4, Czech Republic. 6
State University of New York at Stony Brook,
New York 11733, USA. 7
Scios Inc., Sunnyvale, California
94086, USA.
Correspondence should be addressed to Timothy J. Aitman taitman@ic.ac.uk
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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