Droplets preventing the overflow; PLIN5-coated lipid droplets in insulin sensitivity and mitochondrial function
Skeletal muscle of type 2 diabetes mellitus (T2DM) patients is characterized by high levels of intramyocellular lipid, which associates with insulin resistance and mitochondrial dysfunction. These associations have long been attributed to cellular accumulation of toxic lipid intermediates. However, a new picture is emerging that lipid droplets (LDs) sequester toxic lipid intermediates, thereby inhibiting negative effects on mitochondria and insulin sensitivity. Recently, LD coat protein PLIN5 has been shown to promote lipid storage, without deteriorating insulin sensitivity, while both oxidative gene expression and interaction of LDs with mitochondria are promoted. Moreover, pilot data using newly developed microscopical approaches suggests that increased storage of lipids in PLIN5-coated LDs protects against physiological (fasting-mediated) insulin resistance and mitochondrial dysfunction. Furthermore, pilot data show that overexpression of PLIN5 leads to changes in LD ‘phenotype’ (i.e. density, size and lipid composition). We hypothesize that differences in PLIN5 coating affect LD phenotype which subsequently underlies differences in mitochondrial function and insulin sensitivity in case of similar levels of intramyocellular lipid.
In this project, we aim to:
- identify differences in PLIN5 coating and LD phenotype in populations discrepant in intramyocellular lipid levels, insulin sensitivity and mitochondrial function;
- investigate if PLIN5 plays a role in exercise induced improvement of insulin sensitivity and mitochondrial dysfunction;
- study the involvement of PLIN5 in tethering LDs to mitochondria, using novel state-of-the-art microscopic techniques.
Unraveling the connections between LD coating, LD phenotype, mitochondrial function and insulin sensitivity can identify novel intervention targets for the treatment of insulin resistance and T2DM.
This project is financed by a grant from NUTRIM, school for Nutrition and Metabolism
Phd students: Sabine Daemen, Anne Gemmink