The microenvironment matters: the secret life of intramuscular lipid droplets

In life, it is often the microenvironment, the immediate small-scale exposures, which dictates one’s experiences rather than the overall macroenvironment. In parallel, the macroenvironment of intramyocellular lipid (IMCL) is distinct from the lipid droplet (LD) microenvironment. This microenvironment affects the LD response to various exposures and their association with metabolic outcomes.

Nuances in the LD microenvironment have been used to explain the ‘Athlete’s paradox’ whereby IMCL negatively correlates with insulin sensitivity in sedentary subjects but is associated with high insulin sensitivity in endurance athletes (Goodpaster et al. 2001). In an article in this issue of The Journal of Physiology, Whytock and colleagues use sophisticated histochemical techniques to identify the microenvironment of muscle LDs in response to a 7-day high-fat, high-calorie (HFHC) diet (Whytock et al. 2020). The investigators focus on the effects of HFHC on localization of LDs between muscle fibre types, between central and peripheral cellular regions, and specifically on LD colocalization with the perilipin (PLIN) family of LD proteins.

Several key findings were noted. First, the HFHC diet increased the storage of lipids preferentially in type I fibres, which extends earlier work showing acute physiological increase of free fatty acid levels from lipid infusion results in preferential lipid accumulation of LDs in type I fibres (Chow et al. 2017). Second, in type I fibres, the HFHC diet did not affect central vs. peripheral distribution of PLIN proteins, LDs or PLIN-coated LDs. Lastly, in type I fibres, HFHC feeding increased PLIN3 protein content, but not PLIN3 positive LDs, whereas the HFHC diet did not alter PLIN2 protein content but increased PLIN2-positive LDs (Whytock et al.). The effect of HFHC feeding on the PLIN-LD relationship is particularly notable, as these findings highlight the discrepancy between PLIN protein levels and their localization with specific populations of LDs. Certainly, the extent to which LDs already have PLINs present or acquires new PLINs will dictate the microenvironment and therefore the metabolism and signalling properties of LDs.

In particular, PLIN2 plays an important role in lipid storage. In muscle, in vitro and in vivo PLIN2 overexpression increases LD accumulation whereas in vitro PLIN2 knockdown reduces LD formation (Bosma et al. 2012). In the current paper, the HFHC diet increases muscle PLIN2-positive LDs while muscle diacylglycerol and ceramide, key intermediates capable of triggering cellular dysfunction, remained unchanged (Whytock et al.). These observations support the role of free fatty acid sequestration in modifying the metabolic effect of high-fat exposure. Whether exposure to a HFHC diet in the longer term results in similar findings remains plausible, yet unexplored.

The histochemical demonstration of the LD microenvironment by the current study (Whytock et al.) complements the observation that subcellular compartmentalization of lipid metabolites is associated with discrepant metabolic measures (Perreault et al. 2018). The study by Perreault et al. used differential centrifugation to separate muscle biopsies into sarcolemmal, cytosolic, mitochondrial/endoplasmic reticulum (ER) and nuclear compartments. The investigators found that the association between diacylglycerol (DAG), ceramides and sphingomyelin with whole-body insulin sensitivity depended on the subcellular compartment. As an example, mitochondrial/ER 1,2-DAG correlated positively with insulin sensitivity, whereas sarcolemmal 1,2-DAG did not correlate with insulin sensitivity (Perreault et al. 2018).

In short, the microenvironment inhabited by lipid droplets influences their metabolic impact. This is supported by previous work using differential centrifugation to study subcellular compartmentalization (Perreault et al. 2018) and augmented by the current study using histochemistry to evaluate the PLIN–LD relationship (Whytock et al.). By demonstrating that PLIN proteins may localize to LDs already decorated with PLIN proteins or newly decorate LDs, Whytock et al. establish a novel direction for further exploration of PLIN proteins in muscle lipid metabolism (Whytock et al.). The natural next step would be to describe the mechanisms that affect PLIN localization and how targeting specific PLIN proteins to LDs consequently impacts organelle-organelle interactions and LD metabolism and signalling. Ultimately, the translational step would be identification of sustainable interventions that will augment the LD microenvironment in a favourable and durable manner.