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 obesity 1, 2, 3, 4, 5. In experimental crosses, quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism in adipocytes 5, as well as hypertension 6 and hypertriglyceridaemia 7, 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 Japan 9 (SHR/Izm), and question the aetiological relevance of the Cd36 mutation to insulin resistance in SHR.

We initially searched for genes that were differentially expressed between SHR and its genetic control, the Wistar Kyoto (WKY) rat. Of the 500 independent clones obtained by subtraction analysis of adipocyte cDNA from NIH-derived strains (SHR/NCrj and WKY/NCrj), 2 contained partial cDNA sequences of Cd36 (ref. 10), the rat homologue of human CD36. Northern-blot analysis showed the presence of aberrant Cd36 mRNA in SHR/NCrj, but not in SHR/Izm (Fig. 1a). Cd36 cDNA from SHR/NCrj contained multiple sequence variants as reported 8, whereas Cd36 cDNA from SHR/Izm was normal. Genotype analysis demonstrated that the Cd36 mutation was not present in any of the original SHR/Izm strains, but was found in all NIH-derived strains examined (Fig. 1b).