CD36 (fatty acid translocase) is involved in highaffinity peripheral fatty acid uptake. Mice lacking CD36 exhibit increased plasma free fatty acid and triglyceride (TG) levels and decreased glucose levels. Studies in spontaneous hypertensive rats lacking functional CD36 link CD36 to the insulin-resistance syndrome. To clarify the relationship between CD36 and insulin sensitivity in more detail, we determined insulin-mediated whole-body and tissue-specific glucose uptake in CD36-deficient (CD36 ؊ / ؊ ) mice. Insulinmediated whole-body and tissue-specific glucose uptake was measured by D -[ 3 H]glucose and 2-deoxy-D -[1-3 H]glucose during hyperinsulinemic clamp in CD36 ؊ / ؊ and wild-type control littermates (CD36 ؉ / ؉ ) mice. Whole-body and muscle-specific insulin-mediated glucose uptake was significantly higher in CD36 ؊ / ؊ compared with CD36 ؉ / ؉ mice. In contrast, insulin completely failed to suppress endogenous glucose production in CD36 ؊ / ؊ mice compared with a 40% reduction in CD36 ؉ / ؉ mice. This insulin-resistant state of the liver was associated with increased hepatic TG content in CD36 ؊ / ؊ mice compared with CD36 ؉ / ؉ mice (110.9 ؎ 12.0 and 68.9 ؎ 13.6 g TG/mg protein, respectively). Moreover, hepatic activation of protein kinase B by insulin, measured by Western blot, was reduced by 54%. Our results show a dissociation between increased muscle and decreased liver insulin sensitivity in CD36 ؊ / ؊ mice.

Abstract-It has previously been reported that mice lacking the VLDL receptor (VLDLRϪ/Ϫ) exhibit normal plasma lipid levels and a modest decrease in adipose tissue mass. In the present study, the effect of VLDLR deficiency on profound weight gain was studied in mice. Obesity was induced either by feeding of a high-fat, high-calorie (HFC) diet or by crossbreeding mice onto the genetically obese ob/ob background. After 17 weeks of HFC feeding, VLDLRϪ/Ϫ mice remained lean, whereas their wild-type littermates (VLDLRϩ/ϩ) became obese. Similarly, the weight gain of ob/ob mice was less profound in the absence of the VLDLR. Moreover, VLDLR deficiency led to increased plasma triglycerides after HFC feeding. The protection from obesity in VLDLRϪ/Ϫ mice involved decreased peripheral uptake of fatty acids, because VLDLRϪ/Ϫ mice exhibited a significant reduction in whole-body free fatty acid uptake, with no clear differences in food intake and fat absorption. These observations were supported by a strong decrease in average adipocyte size in VLDLRϪ/Ϫ mice of both obesity models, implying reduced adipocyte triglyceride storage in the absence of the VLDLR. These results suggest that the VLDLR plays a role in the delivery of VLDL-derived fatty acids into adipose tissue. The most striking features that distinguish the VLDLR from the LDLR are (1) 8 ligandbinding repeats instead of 7 and (2) its expression pattern among tissues. The VLDLR is highly expressed in skeletal muscle, heart, and adipose tissue and only in trace amounts in the liver, whereas the LDLR is abundantly expressed in the liver. 1,2 A role for the VLDLR in lipoprotein metabolism has been suggested by in vitro experiments showing that the VLDLR binds and internalizes particles that are rich in apolipoprotein (apo) E, such as VLDL, IDL, and chylomicrons. 1,3 The binding of these lipoprotein particles to the VLDLR was stimulated by lipoprotein lipase (LPL) 3,4 and inhibited by a 39-kDa protein named the receptor-associated protein (RAP). 5 In addition to lipoproteins, the VLDLR has been shown to bind several other ligands, including urokinase complexed to its inhibitor, plasminogen activator inhibitor type 1, 6 and thrombospondin-1. 7 Based on its binding characteristics, endothelial localization, 8 and tissue expression pattern, it is hypothesized that the VLDLR facilitates the binding of triglyceride (TG)-rich particles in the capillary bed and subsequent delivery of free fatty acids (FFAs) to tissues active in fatty acid metabolism. 3,9,10 In line with this hypothesis, it was shown in mice that VLDLR mRNA levels are upregulated in heart and downregulated in adipose tissue after prolonged fasting. 11Reciprocally, VLDLR mRNA levels were downregulated in heart and upregulated in adipose tissue of LDLR-deficient mice fed an atherogenic diet. 12 To directly investigate a role for the VLDLR in lipid metabolism, mice were generated lacking the VLDLR by gene targeting. 13 VLDLRϪ/Ϫ mice exhibited no differences in plasma lipoproteins, and the sole abnormality detected was...

CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient ( cd36 ؊ / ؊ ) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36 ؊ / ؊ mice. cd36 ؊ / ؊ mice showed no differences in hepatic VLDL-TG production or intestinal [ 3 H]TG uptake compared with wild-type littermates. cd36 ؊ / ؊ mice showed a 2-fold enhanced postprandial TG response upon an intragastric fat load ( P Ͻ 0.05), with a concomitant 2.5-fold increased FFA response ( P Ͻ 0.05), suggesting that the increased FFA in cd36 ؊ / ؊ mice may impair LPL-mediated TG hydrolysis. Postheparin LPL levels were not affected. However, the in vitro LPL-mediated TG hydrolysis rate as induced by postheparin plasma of cd36 ؊ / ؊ mice in the absence of excess FFA-free BSA was reduced 2-fold compared with wild-type plasma ( P Ͻ 0.05). This inhibition was relieved upon the addition of excess FFA-free BSA. Likewise, increasing plasma FFA in wild-type mice to the levels observed in cd36 ؊ / ؊ mice by infusion prolonged the plasma half-life of glycerol tri[ 3 H]oleate-labeled VLDL-like emulsion particles by 2.5-fold ( P Ͻ 0.05). We conclude that the increased plasma TG levels observed in cd36 ؊ / ؊ mice are caused by decreased LPL-mediated hydrolysis of TG-rich lipoproteins resulting from FFA-induced product inhibition of LPL. is abundant in peripheral tissues active in FFA metabolism, such as adipose tissue, skeletal muscle, and cardiac muscle, where it is involved in high-affinity uptake of FFA (1, 6, 7). To directly investigate a role for CD36 in lipid metabolism, mice lacking CD36 were generated by gene targeting (8). These CD36-deficient ( cd36 Ϫ / Ϫ ) mice exhibited increased plasma FFA and triglyceride (TG) levels (8). Coburn et al. (9) showed that FFA uptake was considerably impaired in muscle and adipose tissue of cd36 Ϫ / Ϫ mice. Febbraio et al. (8) further showed that the increase in plasma TG levels in the absence of CD36 was primarily attributable to an increase in VLDL-sized particles. Although these data suggest a role for CD36 in TG metabolism in addition to FFA metabolism, the exact mechanisms underlying the increased TG levels in cd36 Ϫ / Ϫ mice are unknown. It has been discussed by Hajri et al. (10) that the VLDL production rate may be enhanced in cd36 Ϫ / Ϫ mice, but the increased plasma TG levels may also be attributable to increased intestinal lipid absorption or to decreased LPL-mediated TG clearance from the circulation.Therefore, the aim of the present study was to elucidate the cause of the hypertriglyceridemia in cd36 Ϫ / Ϫ mice in vivo. Our results show that the increased plasma TG levels in cd36 Ϫ / Ϫ mice are caused by a decreased TG hydrolysis rate rather than by differences in the production of hepatic VLDL-TG or intestinal lipid absorption. From the present study, we conclude that the hypertriglyceridemia observed in cd36 Ϫ / Ϫ mice is caused by decreased LPLmediated hydrolysis of TG-rich lipoproteins resulting ...

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