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...

Leptin has been shown to acutely stimulate fatty acid oxidation and triacylglycerol hydrolysis in skeletal muscle. These effects are similar to those induced by muscle contraction alone. Several studies have demonstrated that, during aerobic exercise, plasma leptin concentrations are well maintained; however, none has examined whether the stimulatory effects of leptin and contraction on muscle lipid metabolism are additive. This is the first study to examine the direct effect of leptin on lipid and carbohydrate (CHO) metabolism in isolated oxidative muscle over a range of contraction intensities. We examined the effect of leptin (10 microg/ml) on the synthesis and degradation of muscle lipid pools [phospholipid (PL), diacylglycerol (DG), triacylglycerol (TG)] and palmitate oxidation in isolated resting and contracting (2, 8, and 20 tetani/min) soleus muscles. At rest, leptin increased fatty acid oxidation (+ 40%, P < 0.05) and TG hydrolysis (+ 47%, P < 0.05), while blunting TG esterification (-20%, P < 0.05). Glucose oxidation was unaffected at rest in the presence of leptin. During tetanic contraction, fatty acid oxidation (+20-114%, P < 0.05) and TG esterification (+ 19-33%, P < 0.05) as well as net TG utilization (+ 23%, P < 0.05) were all significantly increased. However, leptin was without further effect on any of these parameters during contraction. Net utilization of intramuscular glycogen, as well as glucose oxidation, was unaffected during contraction by leptin. The findings of the present study indicate that leptin has an important influence on lipid metabolism in resting muscle, but not during contraction.