Diacylglycerol kinase ε deficiency preserves glucose tolerance and modulates lipid metabolism in obese mice

Abstract

Diacylglycerol kinases (DGKs) catalyze the phosphorylation and conversion of diacylglycerol (DAG) into phosphatidic acid. DGK isozymes have unique primary structures, expression patterns, subcellular localizations, regulatory mechanisms, and DAG preferences. DGKε has a hydrophobic segment that promotes its attachment to membranes and shows substrate specificity for DAG with an arachidonoyl acyl chain in the sn-2 position of the substrate. We determined the role of DGKε in the regulation of energy and glucose homeostasis in relation to diet-induced insulin resistance and obesity using DGKε-KO and wild-type mice. Lipidomic analysis revealed elevated unsaturated and saturated DAG species in skeletal muscle of DGKε KO mice, which was paradoxically associated with increased glucose tolerance. Although skeletal muscle insulin sensitivity was unaltered, whole-body respiratory exchange ratio was reduced, and abundance of mitochondrial markers was increased, indicating a greater reliance on fat oxidation and intracellular lipid metabolism in DGKε KO mice. Thus, the increased intracellular lipids in skeletal muscle from DGKε KO mice may undergo rapid turnover because of increased mitochondrial function and lipid oxidation, rather than storage, which in turn may preserve insulin sensitivity. In conclusion, DGKε plays a role in glucose and energy homeostasis by modulating lipid metabolism in skeletal muscle.

Diacylglycerol kinase α deficiency alters inflammation markers in adipose tissue in response to a high-fat diet

“…The presence of multiple DGKs suggest isoform-specific physiological roles for individual DGK isoforms. For example, DGK deficiency is associated with peripheral insulin resistance and obesity (8), whereas DGK ablation preserves glucose tolerance and modulates lipid metabolism (30). The opposing metabolic phenotypes observed between these KO models further reinforce that notion that isoform-specific actions of DGK may influence metabolism.…”

“…In contrast to other DGK isoform-specific KO mouse models including DGK, DGK, and DGK (8,30,49), the metabolic phenotype of DGK KO mice is subtle. Several of the assays utilized in this study have also been applied to other DGK isoform-specific KO mouse models.…”

“…DGK protein abundance is reduced in skeletal muscle of type 2 diabetic patients (8) with expression regulated by glucose and free fatty acid levels (8,42). We have also determined the role of DGK on glucose and energy homeostasis (30). In contrast with the insulin resistant phenotype observed in the DGK deficient mice (30), DGK KO led to increased glucose tolerance, reduced whole-body respiratory exchange ratio, and increased abundance of mitochondrial markers in skeletal muscle, indicating a greater reliance on fat oxidation and intracellular lipid metabolism (30).…”

“…We have also determined the role of DGK on glucose and energy homeostasis (30). In contrast with the insulin resistant phenotype observed in the DGK deficient mice (30), DGK KO led to increased glucose tolerance, reduced whole-body respiratory exchange ratio, and increased abundance of mitochondrial markers in skeletal muscle, indicating a greater reliance on fat oxidation and intracellular lipid metabolism (30). In cultured MIN6 cells, DGK siRNA attenuates insulin secretion (43), implicating a role for this isoenzyme in type 2 diabetes.…”

Deletion of diacylglycerol kinase ε confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes

“…In skeletal muscles, no changes in insulin signaling or glycogen deposition were induced in DGKe 2/2 mice. Recently, Mannerås-Holm et al (47) performed lipidomic analysis in skeletal muscle of HFDfed DGKe 2/2 mice. The authors found that elevated unsaturated and saturated DG species in DGKe-deficient skeletal muscle, although insulin sensitivity remained unaltered in this tissue.…”