Cachexia continues to represent a therapeutic challenge in cancer patients. The syndrome is a complex process characterised by weight loss and is associated with increased morbidity and mortality [
1,
2]. Whilst both lean and adipose tissue become depleted, there is evidence that body fat is lost more rapidly than lean tissue [
3]. The drivers of lipolysis or possibly reduced lipogenesis [
4] in cancer cachexia are still to be elucidated fully. However, TNFα [
5], ZAG [
6,
7] and MIC-1 [
8] have been suggested as potential mediators. Adipose tissue is composed predominately of stored lipid droplets [
9] and is intimately involved with energy homeostasis and metabolism through secreted adipokines [
10]. Additionally, it influences insulin sensitivity, affects immune and inflammatory pathways and interacts with catecholamines [
11,
12]. The catabolism of lipids generates fatty acids that can either be utilised by skeletal muscle or further metabolised to take part in the Krebs cycle [
9]. Triglyceride-containing lipid droplets are dynamic organelles stored on demand in all cells and grow through a fusion process mediated by SNARE proteins, including SNAP23 [
13]. Within skeletal muscle, it is thought that intramyocellular lipid/lipid droplets act as fuel stores for mitochondrial fat oxidation [
14]. Lipid droplets are usually in direct contact with mitochondria presumably to allow rapid transport when required in situations such as exercise [
14]. Indeed, intramyocellular lipid decreases upon acute exercise [
15‐
18] and almost completely disappears after marathon running [
19,
20]. Conversely, physical inactivity and a diet excessive in fats can lead to an increase in intramyocellular lipid [
18]. Endurance training causes a rise in intramyocellular lipid content supporting the role of lipid droplets as an energy source during physical activity [
14]. Although the presence of lipid droplets in skeletal muscle is part of the normal physiology of healthy individuals with or without physical training, associations have been shown between increased droplet number and pathological states such as the presence of type 2 diabetes/insulin resistance [
14,
21] and ageing [
22]. With ageing, not only are numbers of lipid droplets increased, but their association with mitochondria appears to be disrupted [
22] and mitochondrial function is altered [
23,
24]. In the morbidly obese, raised intramyocellular lipid content has been reported to be associated with insulin resistance and to decrease after weight loss/bariatric surgery [
25,
26]. In patients with gastrointestinal cancer, increased levels of intramyocellular lipid have also been reported. Using magnetic resonance spectroscopy, a 35% higher level of intramyocellular lipids was observed in patients with cachexia (defined by >10% weight loss in previous 6 months) compared with weight-stable cancer patients [
27].
We sought to carry out a quantitative morphological examination of lipid droplets in human cancer-associated weight loss using electron microscopy. We hypothesised that due to the phenotype associated with cancer cachexia (lipid mobilisation, insulin resistance [
4], systemic inflammation [
28], sarcopenia [
29] and reduced physical activity [
30]), there would be an association between increasing weight loss and the number/size of intra-myocellular lipid droplets. Additionally, we examined the relationship between lipid droplets, anthropometry and/or CT-derived body composition measures.