CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice

Abstract

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.

CD36: Implications in cardiovascular disease

“…Under hyperinsulinemic conditions, again, CD36 KO mice showed increased whole body glucose uptake and oxidation (Goudriaan, et al, 2003). Interestingly, hepatic glucose production was not inhibited, as one would expect under these conditions (Goudriaan, et al, 2003). Analysis of tissue uptake of labeled glucose showed a significant increase in uptake in cardiac muscle in CD36 KO mice, consistent with our hypothesis that absence of fatty acid uptake by CD36 in heart leads to altered substrate utilization for energy and the fasting hypoglycemia.…”

“…In fact, using the euglycemic clamp technique, CD36 KO mice showed slightly higher whole body glucose uptake, oxidation and lower glucose storage at basal conditions when compared with background matched wild type control mice (Goudriaan, et al, 2003). Under hyperinsulinemic conditions, again, CD36 KO mice showed increased whole body glucose uptake and oxidation (Goudriaan, et al, 2003).…”

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

“…In line with these studies, it has been demonstrated that CD36 knockout mice have improved insulin sensitivity in muscle, implying that fatty acid flux into the cells plays a critical role in insulin resistance [9]. Several studies investigated the effect of various NEFAs on insulin signalling and glucose metabolism in vitro using different cell lines [10][11][12][13].…”

Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration

“…The following animals (all from Charles River Breeding Laboratories) were infected with the transgenic parasite lines: Swiss mice (male͞ female, 6 weeks old); C57BL͞6 (females, 6 weeks old); BALB͞c (female, 6 weeks old); Wistar rats (female, 11 weeks old); Spontaneous Hypertensive (SHR)͞NCrlBR rats (female, 8 weeks old) deficient in CD36 expression (14,15); Wistar-Kyoto (WKY)͞ NCrlBR rats (female, 8 weeks old) that serve as control for the SHR rats with normal CD36 expression; CD36-null C57BL͞6 (CD36 Ϫ/Ϫ ) mice (female, 8-16 weeks old) deficient in CD36 expression (16,17); wild-type control CD36 ϩ/ϩ C57BL͞6 littermates of the CD36 Ϫ/Ϫ mice (female, 8-16 weeks old); and Grammomys surdaster (male͞female, 6-12 weeks old), obtained from a breeding colony at the Institute of Tropical Medicine (Antwerp) (18). Synchronized infections of P. berghei in rodents (in vivo) and synchronized in vitro cultures were established as described in refs.…”