A triheptanoin diet has high glycogenic potential and stimulates glycogen accumulation in the liver of very long chain acyl-CoA dehydrogenase (VLCAD) knock-out mice, a model of VLCAD deficiency, according to a study presented at the 2023 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM). 

These mice use glycogenic substrates in different ways and this acts as a switch in substrate utilization as a compensatory mechanism, said Siti Nurjanah, MSc who presented the study. Glycerol is used as a precursor for glucose production and heptanoate likely replenishes the tricarboxylic acid (TCA) cycle intermediates, she explained.

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To better understand the effect of impaired long chain fatty acid oxidation on glucose homeostasis, Nurjanah and colleagues conducted 2 sets of experiments.

In the first experiment, they investigated the effect of long-term dietary treatment with different diets on glucose homeostasis in VLCAD deficient mice and in the second experiment, they evaluated the use of glycerol and heptanoate for glycogenesis in these animals.

They found that hepatic glycogen is crucial in maintaining glucose homeostasis in VLCAD deficiency and that long-term triheptanoin diet can compensate for low glycogen levels overall replenishing hepatic glycogen.

Moreover, like with normal chow diet, long-term high protein diet leads to lower hepatic glycogen  content in VLCAD deficient mice and longer fasting periods may therefore result in hypoglycemia, Nurjanah said.

The researchers also found that VLCAD deficient mice did not have impaired TCA cycle intermediates suggesting that the role of anaplerotic substrate in fatty acid oxidation disorder should be investigated further. 

Through the second set of experiments, the researchers demonstrated that heptanoate metabolism was induced in VLCAD deficient mice via the TCA cycle. Using a computational model, they have shown that heptanoate supplementation did not affect total glucose utilization in peripheral tissues and glycerol consumption in the liver of these mice, nor did it affect the concentration of TCA cycle intermediates.

VLCAD deficiency is one of 6 types of long-chain fatty acid oxidation disorders (LCFAOD) caused by a mutation in the ACADVL gene, which encodes for the VLCAD enzyme, which is required for the beta oxidation of fatty acids inside the mitochondria.


Nurjanah S. Modification of dietary substrates impact glucose homeostasis in very long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice. Lecture presented at the International Network for Fatty Acid Oxidation Research and Management (INFORM) 2023 lecture series: May 15, 2023; Virtual.