Metabolomics finds PanK4 to be an Important Regulator of Glucose Uptake and Lipid Metabolism

The Challenge: Promoting metabolic flexibility in skeletal muscle to battle insulin resistance

Skeletal muscle (SkM) helps maintain normal blood sugar levels by internalizing glucose via insulin and then storing it as glycogen. Excessive amounts of glucose and fatty acids caused by prolonged overeating impair mitochondrial function, which leads to insulin resistance and disrupted uptake of glucose and fatty acid oxidation. Pantothenate kinase 4 (PanK4) is an understudied and unique signaling molecule, which lacks classical kinase activity, but instead acts as a phosphatase in certain metabolic pathways that enhance glucose uptake during exercise. With the long-term goal of identifying new therapeutic targets for lowering blood sugar and increasing insulin sensitivity, Miranda-Cervantes and colleagues aimed to characterize the metabolic function of PanK4 in SkM.¹

Metabolon’s Insight: Elucidate the role of PanK4 in glucose metabolism and fatty acid oxidation in skeletal muscle

To gain insight into the metabolic function of PanK4 in exercise-induced metabolic changes, SkM-specific PanK4 knockout (PanK4-/-) and wildtype (PanK4+/+) mice were subjected to treadmill running for set times and paces to simulate maximal running capacity and endurance running. Glucose uptake after exercise was measured in tail vein blood. Mice were euthanized shortly after the exercise bout and SkM tissue samples were analyzed using Metabolon’s Global Discovery Panel.

The Solution: PanK4 is a regulator of glucose uptake and fatty acid oxidation

Despite normal levels of precursor fatty acids and carnitine, most fatty acyl carnitines were lower in PanK4-/- muscles. The analysis of fatty acid oxidation pathways showed this was due to the shunting of fatty acids towards storage pathways rather than oxidization, suggesting that PanK4 regulates fatty acid utilization in SkM by promoting their oxidation.

Typically, acetyl-CoA levels regulate the flux of glucose and fatty acids. Metabolomics data showed that SkM acetyl-CoA levels were significantly elevated in PanK4-/- mice. Elevated levels of citrate and malonyl CoA in PanK4-/- mice were also observed. These findings suggest that the absence of PanK4 leads to higher levels of acetyl-CoA and malonyl-CoA, which could impair fatty acid oxidation by decreasing carnitine shuttle-mediated entry of long-chain fatty acids into mitochondria.

Acetyl-CoA levels have been linked to regulation of glucose metabolism by allosterically inhibiting pyruvate dehydrogenase (PDH), an enzyme that facilitates the conversion of pyruvate to acetyl-CoA. Indeed, activity of PDH trended lower in PanK4-/- mice than in controls, even when PDH was in its active form, showing that PanK4 may regulate the metabolism of glucose in addition to metabolism of lipids. This hypothesis was supported by impaired exercise-induced glucose uptake into PanK4-/- SkM as indicated by higher post-exercise blood glucose levels compared to controls. This phenomenon was observed after both maximum capacity and endurance running. Following exercise, SkM acetyl-CoA and citrate concentrations were also higher in PanK4-/- mice that in controls. Overexpressing PanK4 in PanK4-/- mice rescued glucose uptake and normalized SkM acetyl-CoA levels.

The Outcome: A novel potential therapeutic target is identified and characterized

Overall, the findings of this study demonstrate PanK4 as an important regulator of glucose uptake and glucose and lipid metabolism in response to exercise. By advancing our mechanistic understanding of exercise-induced changes to metabolism, novel therapeutic targets can be identified that may aid in the treatment of insulin resistance and other obesity-driven metabolic disturbances.