Identification of Cd36 (Fat) as an Insulin-Resistance Gene Causing Defective Fatty Acid and Glucose Metabolism in Hypertensive Rats

Nat Genet. 1999 Jan;21(1):76-83. doi: 10.1038/5013.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • CD36 Antigens / metabolism*
  • Cell Membrane / metabolism
  • Chromosome Mapping
  • DNA, Complementary
  • Fatty Acids / metabolism*
  • Fatty Acids, Nonesterified / metabolism
  • Female
  • Gene Deletion
  • Gene Duplication
  • Gene Expression
  • Genetic Linkage
  • Genetic Variation
  • Glucose / metabolism*
  • Humans
  • Hypertension / metabolism*
  • Insulin Resistance / genetics*
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Organic Anion Transporters*
  • Quantitative Trait, Heritable
  • Rats
  • Rats, Inbred SHR
  • Triglycerides / metabolism

Substances

  • CD36 Antigens
  • DNA, Complementary
  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Membrane Glycoproteins
  • Organic Anion Transporters
  • Triglycerides
  • Glucose

Associated data

  • GENBANK/AF111268