Increasing evidence has implicated the membrane protein CD36 (FAT) in binding and transport of long chain fatty acids (FA). To determine the physiological role of CD36, we examined effects of its overexpression in muscle, a tissue that depends on FA for its energy needs and is responsible for clearing a major fraction of circulating FA. Mice with CD36 overexpression in muscle were generated using the promoter of the muscle creatine kinase gene (MCK). Transgenic (MCK-CD36) mice had a slightly lower body weight than control litter mates. This reflected a leaner body mass with less overall adipose tissue, as evidenced by magnetic resonance spectroscopy. Soleus muscles from transgenic animals exhibited a greatly enhanced ability to oxidize fatty acids in response to stimulation/contraction. This increased oxidative ability was not associated with significant alterations in histological appearance of muscle fibers. Transgenic mice had lower blood levels of triglycerides and fatty acids and a reduced triglyceride content of very low density lipoproteins. Blood cholesterol levels were slightly lower, but no significant decrease in the cholesterol content of major lipoprotein fractions was measured. Blood glucose was significantly increased, while insulin levels were similar in the fed state and higher in the fasted state. However, glucose tolerance curves, determined at 20 weeks of age, were similar in control and transgenic mice. In summary, the study documented, in vivo, the role of CD36 to facilitate cellular FA uptake. It also illustrated importance of the uptake process in muscle to overall FA metabolism and glucose utilization.Our previous work with rat adipocytes presented evidence that membrane transport of long chain fatty acids (FA) 1 had a protein-facilitated component (1, 2). We identified an 88-kDa glycoprotein as a candidate FA transporter by labeling with inhibitors of FA transport, notably sulfo-N-succinimidyl derivatives of long chain FA (2, 3). The cDNA, isolated from a rat adipose tissue cDNA library (4), coded for a protein (FAT, for FA translocase), which is the rat homolog of human platelet CD36 (5) and of bovine mammary PASIV (6). FAT/CD36 mRNA is abundant in tissues active in FA metabolism such as heart, skeletal muscle, fat, and intestines (4, 7), and modulated by conditions that alter lipid metabolism, such as diabetes mellitus and high fat feeding (8). In preadipocytes, the mRNA is induced by FA (9, 10), an effect mediated by the nuclear transcription factors peroxisome proliferator-activated receptors (10, 11), which play a role in adipocyte differentiation and possibly obesity (11, 12). CD36 mRNA is also a marker of preadipocyte differentiation, and its early induction, is paralleled with an increase in membrane FA transport (4). More recently, CD36 has been identified as a causal gene at the peak of linkage for defects in FA and glucose metabolism in spontaneously hypertensive rats (13), a rodent model of insulin resistance.There is indirect evidence to support the role of CD36 in muscle F...

Long-chain fatty acids are an important constituent of the diet and they contribute to a multitude of cellular pathways and functions. Uptake of long-chain fatty acids across plasma membranes is the first step in fatty acid utilization, and recent evidence supports an important regulatory role for this process. Although uptake of fatty acids involves two components, passive diffusion through the lipid bilayer and protein-facilitated transfer, the latter component appears to play the major role in mediating uptake by key tissues. Identification of several proteins as fatty acid transporters, and emerging evidence from genetically altered animal models for some of these proteins, has contributed significant insight towards understanding the limiting role of transport in the regulation of fatty acid utilization. We are also beginning to better appreciate how disturbances in fatty acid utilization influence general metabolism and contribute to metabolic pathology.

Genetic linkage studies implicated deficiency of CD36, a membrane fatty acid (FA) transporter, in the hypertriglyceridemia and hyperinsulinemia of the spontaneously hypertensive rat (SHR). In this study we determined whether loss of CD36 function in FA uptake is a primary determinant of the SHR phenotype. In vivo, tissue distribution of iodinated, poorly oxidized ␤-methyliodophenyl pentadecanoic acid (BMIPP) was examined 2 h after its intravenous injection. Fatty acid transport was also measured in vitro over 20 to 120 s in isolated adipocytes and cardiomyocytes obtained from SHR and from a congenic line (SHRchr4) that incorporates a piece of chromosome 4 containing wild-type CD36. SHR heart and adipose tissue exhibited defects in FA uptake and in conversion of diglycerides to triglycerides that are similar to those observed in the CD36 null mouse. However, a key difference in SHR tissues is that fatty acid oxidation is much more severely impaired than fatty acid esterification, which may underlie the 4 -5-fold accumulation of free BMIPP measured in SHR muscle. Studies with isolated adipocytes and cardiomyocytes directly confirmed both the defect in FA transport and the fact that it is underestimated by BMIPP. Heart, oxidative muscle, and adipose tissue in the SHR exhibited a large increase in glucose uptake measured in vivo using [ 18 F]fluorodeoxyglucose. Supplementation of the diet with short-chain fatty acids, which do not require CD36-facilitated transport, eliminated the increase in glucose uptake, the hyperinsulinemia, and the heart hypertrophy in the SHR. This indicated that lack of metabolic energy consequent to deficient FA uptake is the primary defect responsible for these abnormalities. Hypertension was not alleviated by the supplemented diet suggesting it is unrelated to fuel supply and any contribution of CD36 deficiency to this trait may be more complex to determine. It may be worth exploring whether short-chain FA supplementation can reverse some of the deleterious effects of CD36 deficiency in humans, which may include hypertrophic cardiomyopathy.The spontaneously hypertensive rat (SHR) 1 is a widely studied rodent model of human metabolic Syndrome X, in which hypertension is associated with dyslipidemia and with insulin resistance of glucose metabolism (1). Two quantitative trait loci for defective insulin action in the SHR were identified on chromosomes 4 and 12. Quantitative trait loci for defects in glucose and fatty acid metabolism and for hypertension map to the same locus on chromosome 4 (1). Microarray screening and congenic mapping identified CD36 on rat chromosome 4 as a defective SHR gene at the peak of linkage to these quantitative trait loci (2). The SHR CD36 cDNA contains multiple sequence variants and the protein product is undetectable in SHR adipocyte plasma membrane (2).CD36 was identified on platelets (3) as a receptor for thrombospondin, collagen (4), and oxidized lipoproteins (5). CD36 is also known as FAT for fatty acid translocase (6) since its function in long-chain FA ...