Myocellular lipid droplets, insulin sensitivity and mitochondrial function: a microscopic approach
Skeletal muscle of type 2 diabetes mellitus (T2DM) patients is characterized by high levels of intramyocellular lipid (IMCL), which associates with insulin resistance and mitochondrial dysfunction. However, endurance trained athletes also have high levels of IMCL, whilst being highly insulin sensitive. This is also termed the “athlete’s paradox”.
This paradox has long been attributed to differential cellular accumulation of toxic lipid intermediates. Using the mass spectrometry technique of MALDI we aim to further elucidate differences in lipid subspecies in the muscle at a fiber specific level between athletes and T2DM patients. Furthermore, using CARS microscopy we are able to look at differences in lipid characteristics at a lipid droplet (LD) specific level.
LDs are the main lipid storage compartment in the muscle. However, a new picture is emerging that LDs are not just storage organelles, but are highly dynamic and may be important for sequestering toxic lipid intermediates, thereby inhibiting negative effects on mitochondria and insulin sensitivity. There are indications that LD morphology, localization and interaction with other organelles, mainly mitochondria, maybe related to development of insulin sensitivity. Using confocal microscopy we aim to identify differences in LD morphology, localization and interaction with mitochondria in populations discrepant in IMCL levels, insulin sensitivity and mitochondrial function. Furthermore, we aim to elucidate the dynamics of LDs with different interventions, for example exercise training, and whether this relates to improvements in insulin sensitivity and mitochondrial function.
Additionally, the proteins present at the surface of the LD appear to have an important regulatory function. Our main protein of interest is perilipin 5 (PLIN5). This LD coat protein has been shown to promote lipid storage, without deteriorating insulin sensitivity, while oxidative gene expression and interaction of LDs with mitochondria are both promoted. Moreover, we have previously shown that increased storage of lipids in PLIN5-coated LDs protects against physiological (fasting-mediated) insulin resistance and mitochondrial dysfunction. Therefore, we aim to elucidate whether PLIN5 coating of LDs might (partly) explain the athlete’s paradox. Moreover, using high-resolution STED microscopy we aim to further study the cellular localization of PLIN5 and the putative involvement of PLIN5 in tethering LDs to mitochondria.
Unraveling the connections between LD phenotype, LD coating, mitochondrial function and insulin sensitivity can identify novel intervention targets for the treatment of insulin resistance and T2DM.
This project is financed by Diabetes Fonds, NUTRIM, CVON, EFSD
Principal investigator: Matthijs Hesselink
Postdoc: Anne Gemmink
PhD students: Sabine Daemen, Nynke van Polanen