DGKζ deficiency protects against peripheral insulin resistance and improves energy metabolism

Abstract

Diacylglycerol kinases (DGKs) regulate the balance between diacylglycerol (DAG) and phosphatidic acid. DGKζ is highly abundant in skeletal muscle and induces fiber hypertrophy. We hypothesized that DGKζ influences functional and metabolic adaptations in skeletal muscle and whole-body fuel utilization. DAG content was increased in skeletal muscle and adipose tissue, but unaltered in liver of DGKζ KO mice. Linear growth, body weight, fat mass, and lean mass were reduced in DGKζ KO versus wild-type mice. Conversely, male DGKζ KO and wild-type mice displayed a similar robust increase in plantaris weight after functional overload, suggesting that DGKζ is dispensable for muscle hypertrophy. Although glucose tolerance was similar, insulin levels were reduced in high-fat diet (HFD)-fed DGKζ KO versus wild-type mice. Submaximal insulin-stimulated glucose transport and p-Akt Ser were increased, suggesting enhanced skeletal muscle insulin sensitivity. Energy homeostasis was altered in DGKζ KO mice, as evidenced by an elevated respiratory exchange ratio, independent of altered physical activity or food intake. In conclusion, DGKζ deficiency increases tissue DAG content and leads to modest growth retardation, reduced adiposity, and protection against insulin resistance. DGKζ plays a role in the control of growth and metabolic processes, further highlighting specialized functions of DGK isoforms in type 2 diabetes pathophysiology.

Data-Mining Approach on Transcriptomics and Methylomics Placental Analysis Highlights Genes in Fetal Growth Restriction

“…Higher levels of expression of PEA15 have been reported in both patients with diabetes mellitus type 2 (Condorelli et al, 1998) and in euglycemic patients with impaired insulin sensitivity (Valentino et al, 2006). The DGKZ gene, already discussed above, has been proven to play a role in the protection against peripheral insulin resistance and in improving overall energy metabolism (Benziane et al, 2017). SLC2A1, also known as glucose transporter 1 (GLUT1), is the major glucose transporter in the human placenta and the ratelimiting step of glucose transport from the placenta to the fetus (Illsley, 2000).…”

“…Wang et al (Wang et al, 2013) and Yates et al (Yates et al, 2012) already reported that hypoxemia and hypoglycaemia undergone during IUGR decrease muscle mass in offspring. DGKZ (found hypomethylated, overexpressed) is known to induce muscle fiber hypertrophy and plays a role in the adaptation to energy metabolism alterations (Benziane et al, 2017). FOXK1 induces muscle progenitor cell proliferation and inhibits their differentiation (Shi et al, 2012).…”

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

“…In contrast, whole-body deletion of DGKε triggers DAG accumulation in skeletal muscle but improves glucose tolerance [ 44 ]. Lastly, DGKζ KO mice exhibit improved muscle insulin sensitivity [ 45 ]. Altogether, these conflicting results might be explained by the specific subcellular DAG localizations and substrate preferences of the various enzyme isoforms and justify the need to further unravel the mechanisms through which DAGs drive IR.…”

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

“…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.…”