DGKζ deficiency protects against peripheral insulin resistance and improves energy metabolism

Diacylglycerol kinases (DGKs) regulate the balance between diacylglycerol (DAG) and phosphatidic acid. DGK zeta is highly abundant in skeletal muscle and induces fiber hypertrophy. We hypothesized that DGK zeta 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 DGK zeta KO mice. Linear growth, body weight, fat mass, and lean mass were reduced in DGK zeta KO versus wild-type mice. Conversely, male DGK zeta KO and wild-type mice displayed a similar robust increase in plantaris weight after functional overload, suggesting that DGK zeta is dispensable for muscle hypertrophy. Although glucose tolerance was similar, insulin levels were reduced in high-fat diet (HFD)-fed DGK zeta KO versus wildtype mice. Submaximal insulin-stimulated glucose transport and p-Akt Ser(473) were increased, suggesting enhanced skeletal muscle insulin sensitivity. Energy homeostasis was altered in DGK zeta KO mice, as evidenced by an elevated respiratory exchange ratio, independent of altered physical activity or food intake.jlr In conclusion, DGK zeta deficiency increases tissue DAG content and leads to modest growth retardation, reduced adiposity, and protection against insulin resistance. DGK zeta plays a role in the control of growth and metabolic processes, further highlighting specialized functions of DGK isoforms in type 2 diabetes pathophysiology.