Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling

Abstract

During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.

Plasma Cathepsin D Activity Rather Than Levels Correlates With Metabolic Parameters of Type 2 Diabetes in Male Individuals

“…Moreover, we recently found that inhibition of extracellular CTSD activity reduced plasma insulin levels and hepatic lipids in rats with hepatic steatosis ( 18 ). Likewise, our group also previously observed that inhibiting CTSD activity via pepstatin A (an aspartic lysosomal enzymes inhibitor) reduces the gene expression of CD36 (a transporter of FFA) ( 23 ) that also mediates the suppression of FFA on insulin signaling ( 37 ). This data thereby suggests that CTSD activity is likely involved with insulin signaling via regulating FFA metabolic pathways (i.e., CD36 transporter).…”

Endothelial cell CD36 optimizes tissue fatty acid uptake

“…ilar improvements in insulin action or glucose metabolism, and, instead, hearts from these mice had downregulated expression of some glucose uptake genes, opposite to what would be expected with reduced lipid uptake. These changes might reflect myocyte-autonomous actions of CD36 that regulate insulin signaling (45). These separate effects on parenchymal biology could explain the propensity to develop insulin resistance in humans with CD36 mutations (46).…”

The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

“…CD36 interacts with the insulin receptor, thereby promoting tyrosine phosphorylation of the receptor by Fyn kinase and enhancing downstream signaling, causing glucose uptake and utilization. In contrast, the presence of saturated FAs, but not unsaturated FAs, inhibits CD36-Fyn-dependent phosphorylation of the insulin receptor [ 133 ]. Therefore, CD36 influence on muscle fuel choice between FA and glucose depends on the metabolic state.…”

“…Therefore, CD36 influence on muscle fuel choice between FA and glucose depends on the metabolic state. The dysregulation of the CD36-dependent pathways of FA and glucose metabolism in skeletal muscles, occurring in chronic excess of FA and DM, may reduce their ability to modulate FA, and glucose utilization depends on energy needs, which will result in lipid accumulation and insulin resistance [ 130 , 133 ].…”