Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG

Abstract

Type 2 diabetes and skeletal muscle insulin resistance have been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different reactivity in vitro, we investigated whether the described function of DAGs as mediators of lipid-induced insulin resistance was dependent on the different DAG isomers. We measured insulin-stimulated glucose uptake in hormone-sensitive lipase (HSL) knockout (KO) mice after treadmill exercise to stimulate the accumulation of DAGs in skeletal muscle. We found that, despite an increased DAG content in muscle after exercise in HSL KO mice, the HSL KO mice showed a higher insulin-stimulated glucose uptake postexercise compared with wild-type mice. Further analysis of the chemical structure and cellular localization of DAG in skeletal muscle revealed that HSL KO mice accumulated sn-1,3 DAG and not sn-1,2 DAG. Accordingly, these results highlight the importance of taking the chemical structure and cellular localization of DAG into account when evaluating the role of DAG in lipid-induced insulin resistance in skeletal muscle and that the accumulation of sn-1,3 DAG originating from lipolysis does not inhibit insulin-stimulated glucose uptake.

Mechanisms Preserving Insulin Action during High Dietary Fat Intake

“…DAG content was measured on freeze dried liver tissue by thin layer chromatography. Lipids were extracted in chloroform-methanol (2:1) and dissolved in chloroform, before being separated (Serup et al, 2016). Lipid staining were developed by a 10% copper sulfate pentahydrate and 8% phosphoric acid solution at 120 C for 15 min, and visualized and analyzed on a Kodak image station (Kodak 2000MM, DK).…”

The effect of diet and exercise on lipid droplet dynamics in human muscle tissue

“…After a treadmill exercise, knock-out mice showed increased insulinstimulated glucose uptake along with higher (rather than lower) total DAG levels compared with wild-type mice. DAG subtype analysis revealed that 1,3-DAG increased after exercise whereas 1,2-DAG decreased after exercise (Serup et al, 2016).…”

Defining lipid mediators of insulin resistance: controversies and challenges

“…Nevertheless, multiple early studies found that PKC activation is stereospecific and achieved only by sn-1,2 DAGs (Rando & Young 1984, Boni & Rando 1985, Leach et al 1991, Wakelam 1998, Takai et al 2012. The sn-1,3 DAGs found in lipid droplets have no effect on PKC, and indeed their accumulation in muscle has recently been shown in mice to have no negative effects on insulin signalling or glucose uptake (Serup et al 2016, Lundsgaard et al 2017. Likewise, differentiation in human muscle insulin sensitivity has been found to be unrelated to sn-1,3 or sn-2,3 DAGs (Perreault et al 2018).…”

“…Genetic mitochondrial dysfunction in mice also presents contradictory evidence: long-chain acyl-CoA dehydrogenase deficiency leads to hepatic IR (Zhang et al 2007); while defective mitochondrial substrate metabolism induced by deletion of mitochondrial transcription factor A (TFAM), apoptosis inducing factor (AIF), very long-chain acyl-CoA dehydrogenase (VLCAD) or carnitine palmitoyltransferase 2 (CPT2) protects from diet-induced obesity and IR (Wredenberg et al 2006, Pospisilik et al 2007. These discrepancies may well reflect homeostatic compensatory mechanisms responding to either elevated lipid availability or dysfunctional mitochondria (Turner et al 2007, Serup et al 2016. Apparent regulatory redundancies suggest the biological relevance of mitochondrial FAO, regardless of whether its deterioration is a consequence or stimulus of lipid accumulation.…”