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

The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose gen etic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QT Ls) for SHR defects in glucose and fatty acid metabolism, hypertriglycerida emia and hypertension map to a single locus on rat chromosome 4. Here we co mbine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) m apping to identify a defective SHR gene, Cd36 (also known as Fat, as it enc odes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd3 6 cDNA contains multiple sequence variants, caused by unequal genomic recom bination of a duplicated ancestral gene. The encoded protein product is und etectable 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 hypertriglyceridaem ia in SHR and may be important in the pathogenesis of human insulin-resista nce syndromes.