CD36null Mice the Fasting Phenotype

Despite the significant defect in post-prandial FA uptake observed in muscle and adipose tissues of CD36-null mice, there is no compensatory increase in glucose utilization and serum FA and glucose levels are unchanged. However, significant changes are observed when the mice are fasted. In comparison to wild-type controls, fasting levels of plasma free FA and VLDL-triglyceride are significantly increased (2- and 1.4-fold, respectively) and those of plasma glucose [113] and insulin levels (Hajri et al., unpublished observations) are significantly decreased (by 25 and 30%, respectively) in CD36-null mice.

To investigate the underlying mechanisms of this phenotype, differences in FA and glucose uptake between these mice in the basal and fasted states were evaluated with BMIPP and FDG (Coburn et al., unpublished observations). In fasted mice BMIPP uptake was significantly decreased in CD36-null adipose tissue, suggesting that lipolysis may be enhanced in comparison to controls. In CD36-null liver, both FDG and BMIPP uptake were significantly increased with fasting. The increase in FDG uptake is consistent with a previously documented autoregula-tory mechanism whereby hepatic glucose output is inhibited under conditions of hyperlipidemia [119]. In highly oxidative cardiac and diaphragm muscles FDG uptake was dramatically increased (13- and 3-fold, respectively) with fasting, suggestive of a compensatory increase secondary to a decreased rate of FA oxidation. These findings are consistent with previous reports showing that agents such as methylpalmoxirate, which inhibits lipid oxidation, or nicotinic acid, which decreases circulating levels of FA, markedly enhance whole body glucose disposal [120-122]. In rats given methylpamloxirate, FDG uptake was found to be enhanced in heart and diaphragm by about the same extents seen here with no change observed in the white gastrocnemius, a glycolytic muscle [120]. Interestingly, a further study showed that a dramatic increase in the rate of glucose disposal following inhibition of FA oxidation in rats occurred only with fasting [121].

These observations have led us to propose the following model (shown in Fig. 1.5) to explain the CD36-null fasting phenotype. The increased fasting serum FA is likely a result of both increased mobilization from adipose tissue and decreased peripheral FA utilization. The elevation in serum FA increases flux and uptake of FA by the liver. This would increase triglyceride synthesis and incorporation into lipoproteins, as evidenced by the increase in fasting VLDL-triglycer-ide. FA oxidation is significantly decreased in CD36-null oxidative muscle but may be normal in glycolytic muscle due to the increased serum FA concentration and the lower oxidative capacity of this tissue. The presumed increase in hormone-sensitive lipase activity in adipose tissue may result from the fasting hy-poinsulinemia observed in these mice. Circulating levels of cortisol as well as sympathetic activity to adipose depots are also likely to be increased, further stimulating lipolysis. The decrease in insulin secretion may initially occur as a result of the greatly increased glucose disposal by heart and highly oxidative skeletal muscles and may be compounded as the fast progresses and serum FA levels rise

Fig. 1.5 Model of the CD36-null fasting phe-notype. Small up/down arrows denote changes in comparison to fasted wild-type controls. In this model, the major defect is a dramatic increase in glucose uptake by oxidative muscles, compensating for the defect in FA oxidation. This occurs only with fasting and is likely induced by a drop in the energy charge of the cell subsequent to the initial drop in insulin. The resulting hypoglycemia causes a further decrease in insulin secretion and increased sympathetic activity, both of

Fig. 1.5 Model of the CD36-null fasting phe-notype. Small up/down arrows denote changes in comparison to fasted wild-type controls. In this model, the major defect is a dramatic increase in glucose uptake by oxidative muscles, compensating for the defect in FA oxidation. This occurs only with fasting and is likely induced by a drop in the energy charge of the cell subsequent to the initial drop in insulin. The resulting hypoglycemia causes a further decrease in insulin secretion and increased sympathetic activity, both of which would increase lipolysis in adipose tissue. The increased serum FA gives rise to increased FA uptake by liver and subsequently to increased VLDL triglyceride and ketone bodies. At some point the increase in FA uptake by liver induces an autoregulatory mechanism effectively clamping hepatic glucose output and thereby contributing to the hypo-glycemia. This vicious cycle continues, escalating the hypoglycemia and dyslipidemia, as the fast progresses and is only partially compensated for by the rising ketone levels.

by a FA-induced clamping of hepatic glucose output. Although this model is likely to be amended as more data are obtained, it nevertheless illustrates the important regulatory role of CD36 in the homeostatic mechanisms controlling both substrate transfer between tissues and the balance of local substrate utilization.

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