HSL and ATGL: the movers and shakers of muscle lipolysis

Abstract

Intramuscular triglyceride (IMTG) accounts for only a fraction of the total lipid store in the human body. However, given its significant contribution as a substrate for ATP synthesis during exercise, and its proposed role in the development of skeletal muscle insulin resistance, IMTG metabolism has proved to be an area of great scientific interest over the last 20 years. Studies investigating IMTG utilisation during exercise remained equivocal, until methods using immunofluorescence microscopy enabled the muscle fibre type-specific assessment of IMTG content without the interference of extramyocellular adipocytes. Studies using this method convincingly demonstrated that in trained individuals 60-70% of IMTG can be depleted in type I muscle fibres during prolonged moderate-intensity exercise, and can account for up to 50% of total lipid oxidation (van Loon, 2004). Of more clinical relevance were studies highlighting the potential role of intramuscular lipid accumulation in the development of skeletal muscle insulin resistance. This hypothesis has been refined over the last decade, as highly insulin-sensitive, endurance-trained athletes exhibit higher levels of total IMTG and diacylglycerol (DAG) (Amati et al. 2011). It is now hypothesised that the accumulation of ceramides and certain species of membrane-bound DAG are responsible for the inhibition of insulin-mediated glucose uptake. The regulation of intramuscular lipolysis is an important area, given its role in the regulation of fatty acid supply to the mitochondria during exercise and in the determination of skeletal muscle lipid content and composition. However, the precise mechanisms regulating muscle lipolysis remain poorly understood. Hormone-sensitive lipase (HSL) was long considered to be the only enzyme involved in muscle lipolysis, until adipose triglyceride lipase (ATGL) was discovered and found to be expressed in skeletal muscle. As the activities of ATGL and HSL are highly specific for triglyceride (TG) and DAG, respectively, ATGL is now considered to contribute to the initial step in TG hydrolysis, with HSL primarily responsible for the breakdown of DAG.Important and intriguing new data have recently been presented by Alsted et al. (2013), which question the importance of HSL in contraction-mediated lipolysis in skeletal muscle. The authors hypothesised that lipases other than HSL are responsible for IMTG lipolysis during muscle contraction. In a well-designed series of experiments, the authors used a combination of pharmacological HSL inhibition (using a small-molecule inhibitor of HSL; 76-0079, Novo Nordisk, Bagsvaerd, Denmark) and HSL knockout (KO) mice, with an ex vivo electrical stimulation approach, to probe the effects of muscle contraction on IMTG lipolysis in the absence of HSL activity. In addition, they used histochemical methods to measure contraction-induced changes in IMTG content as a surrogate of IMTG lipolysis.First, the study demonstrated that IMTG content decreased following muscle contraction. This is in agreement with the fin...

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The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis

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