Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36-deficient BN.SHR4 congenic rat strain

Abstract

The favorable metabolic effects of thiazolidinediones are supposedly related to the peroxisome proliferator-activated receptor-γ (PPARγ)-driven changes in lipid metabolism, particularly in free fatty acid (FFA) trafficking. The fatty acid translocase CD36 is one of the proposed PPARγ targets to mediate this action. We assessed the effect of rosiglitazone (RSG, Avandia) administration in two inbred rat strains, BN/Cub and BN.SHR4 congenic strain, differing in 10 cM proximal segment of chromosome 4. Rats were fed high-sucrose diet with or without RSG for 1 wk. In BN.SHR4, which carries defective Cd36 allele of SHR origin, RSG failed to improve glucose tolerance (assessed by the oral glucose tolerance test), did not lower triglyceridemia, nor induced increases in epididymal and retroperitoneal adipose tissue weights and adipose tissue glucose utilization, effects observed in BN/Cub. On the other hand, the RSG-treated BN.SHR4 showed lower concentrations of FFA and substantial increase in glycogen synthesis and glucose oxidation in skeletal muscle. Altogether, these results support involvement of CD36 in RSG action, suggesting this pharmacogenetic interaction may be of particular importance in CD36-deficient humans.

Thiazolidinediones improve insulin sensitivity in adipose tissue and reduce the hyperlipidaemia without affecting the hyperglycaemia in a transgenic model of type 2 diabetes

“…Ablation of the CD36 gene in mice inhibited fatty acid uptake into adipose tissue as well as skeletal muscle [38]. Moreover, in CD36-deficient rats the effect of pioglitazone is blunted [36].…”

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

“…The transfer of a limited segment of rat chromosome 4 including the mutated Cd36 gene of SHR origin into the genomic background of PD rat strain elicited an improvement in glucose tolerance, lowering of insulinaemia and shifts in lipid levels contrasting with those reported previously after a similar transfer to Brown Norway genomic background (Seda et al, 2002(Seda et al, , 2003a; Table 5). As we have previously shown the concentrations of insulin, glucose, free fatty acids and cholesterol to be comparable in PD and SHR strains (Sedova et al, 2000), the current results indicate the presence of an interaction between gene(s) within the introgressed segments and genomic background of the congenic strains.…”

“…One of the mechanisms responsible may lie in the fact that human islets express Cd36 in the plasma membrane as well as in the insulinsecretory granules, and Cd36 activity was deemed important for uptake of fatty acids into b-cells as well as for mediating their modulatory effects on insulin secretion (Noushmehr et al, 2005) . Altogether, it is apparent that the eventual metabolic effect of Cd36 deficiency is tightly linked to a particular setting of both genomic background (for example, PD.SHR4 vs BN.SHR4 (Seda et al, 2002(Seda et al, , 2003b; Table 5 and Supplementary Figure 3) and environmental factors, particularly diet (Febbraio et al, 1999;Hajri et al, 2002;Koonen et al, 2007;Kennedy et al, 2011) or medication (Qi et al, 2002;Seda et al, 2003a;Seda et al, 2008;Krupkova et al, 2010). Therefore, the apparently controversial issue of causal relation between level of Cd36 expression and metabolic outcome may be resolved by adoption of broader conceptual framework incorporating other (eco)genomic factors.…”

“…Of those, only Cd36 was found to be differentially expressed between PD and PD.SHR4a. Further studies are needed to assess the effect of Cd36 and the whole differential segment under distinct nutritional and pharmacological challenges, especially given our previous extensive documentation of nutrigenetic and pharmacogenetic interactions of a similar genomic region in the BN.SHR4 congenic strain (Seda et al, 2003a(Seda et al, , 2008Krupkova et al, 2010). In sum, the introduction of mutated Cd36 into the genomic background of an inbred model of metabolic syndrome resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome.…”

“…Furthermore, we have found this limited portion of genome to be crucial for several pharmacogenetic interactions involving the insulin sensitizer rosiglitazone (Seda et al, 2003a(Seda et al, , 2008 and glucocorticoid dexamethasone (Krupkova et al, 2010). In SHR, Cd36 was established as a key determinant of the insulin-sensitizing actions of thiazolidinediones using SHR transgenic and congenic strains expressing wild-type Cd36 (Qi et al, 2002).…”