Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect

Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin—a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone—can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD(−/−)) mice with (13)C(3)-glycerol in the presence and absence of heptanoate (C7). The incorporation of (13)C(3)-glycerol into blood glucose was higher in VLCAD(−/−) mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with (13)C enrichment of liver metabolites in VLCAD(−/−) mice. In contrast, the C7 bolus significantly decreased the (13)C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD(−/−) mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.