Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice

Abstract

IntroductionHigh blood fatty acids (FAs) are a common feature of insulin-resistant states (1), and raising the level of plasma FAs can induce acute insulin resistance (2). Plasma FAs and insulin sensitivity are negatively correlated (2), and an even stronger negative correlation can be documented with intramuscular triglycerides (TGs) (3,4). Randle et al. (5) originally stated that excessive muscle FA oxidation induced insulin resistance by inhibiting glucose oxidation. The mechanism proposed (6) involved inactivation of pyruvate dehydrogenase, phosphofructokinase, and hexokinase. However, recent measurements of muscle concentrations of glucose and glucose-6-phosphate using noninvasive nuclear magnetic resonance spectroscopy indicate that the negative FA effect on glucose utilization may be exerted primarily at the level of membrane transport (7). In addition, the reduction in intracellular glucose utilization associated with transport inhibition appears to mostly reflect a decrease in glucose conversion to glycogen rather than in glucose oxidation (8).A valuable model for the study of the effects of alteration in FA utilization on insulin responsiveness is the recently generated CD36-deficient mouse (9). CD36, also known as fatty acid translocase (FAT) (10), is a multispecific, integral membrane glycoprotein (11, 12) that has been identified as a facilitator of FA uptake. Its function in binding and transport of FA was documented in vitro by affinity labeling with FA derivatives and by cell transfection studies (13). Generation of mice deficient in or overexpressing CD36 established the physiological role of the protein. The CD36-deficient mouse (9, 14) exhibits greater than a 60% decrease of FA uptake and utilization by heart, oxidative skeletal muscle, and adipose tissues. In contrast, mice with muscle CD36 overexpression (15) have enhanced FA oxidation in response to contraction, documenting the rate-limiting role of the transport step.CD36 deficiency has been genetically linked to insulin resistance in the spontaneously hypertensive rat (SHR), a rodent model of human metabolic syndrome X (16,17). Supplementing the diet with short-and medium-chain FA, which would not require CD36-facilitated transport, improves SHR hyperinsulinemia and myocardial hypertrophy (18).In contrast to the findings in the SHR, early data in the CD36-null mouse documented fasting hypoglycemia (9), while muscle CD36 overexpression was associated with hyperglycemia and hyperinsulinemia (15). In humans, although incidence of CD36 Deficiency of the membrane protein FAT/CD36 causes a marked defect in fatty acid uptake by various tissues and is genetically linked to insulin resistance in rats and humans. Here, we examined insulin responsiveness of CD36 -/-mice. When fed a diet high in complex carbohydrates and low (5%) in fat, these animals cleared glucose faster than the wild-type. In vivo, uptake of 2-fluorodeoxyglucose by muscle was increased severalfold, and in vitro, insulin responsiveness of glycogenesis by the soleus was enhanced. ...

Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice

“…However, we did observe that ApoE −/− Nrf2 −/− mice have significantly elevated triglyceride levels. This is consistent with previous studies demonstrating that CD36 -deficient mice have elevated plasma triglyceride levels [34] , [35] , further supporting the role of CD36 in ApoE −/− Nrf2 −/− mice. Mechanisms of the concomitant increase in blood glucose in Nrf2 deficient mice are less clear, although it may be attributed to dyslipidemia-induced insulin resistance.…”

Lipoprotein lipase activity is required for cardiac lipid droplet production

“…This likely indicates an increased reliance on glucose oxidation, i.e., pyruvate conversion to acetyl-CoA. Although gene expression of the glucose transporters GLUT1 and GLUT4 was variable, it has been previously demonstrated that Ppara −/− mice ( 47 ), Cd36 −/− mice ( 48 ), and hLpL0 mice ( 23 ) all have increased cardiac glucose uptake. P407-treated fasting mice, which did not accumulate TGs in cardiomyocytes, tended to have increased glucose uptake.…”

Herbal adaptogens combined with protein fractions from bovine colostrum and hen egg yolk reduce liver TNF-α expression and protein carbonylation in Western diet feeding in rats

“…A plethora of evidence suggests that a lowered Cd36 expression is metabolically protective while overexpression is likely to result in metabolic complications [ 47 , 48 ]. However, evidence also exists suggesting that Cd36 may be integral in glucose metabolism and insulin control [ 49 - 51 ].…”