The mitochondrial β-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial β-oxidation of unsaturated fatty acids, we created a DECR–deficient mouse line. In Decr −/− mice, the mitochondrial β-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr −/− mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C 18:2), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr −/− mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal β-oxidation and microsomal ω-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1α and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.
Fatty acids released from triacylglycerols or obtained from the diet serve as a main energy provider to the heart and skeletal muscle, and when carbohydrates are scarce, fatty acids provide energy for the whole organism. Inherited disorders of mitochondrial β-oxidation are among the most common inborn errors of metabolism affecting infants and children. Under normal conditions, patients are usually asymptomatic; but when challenged with metabolic stress, severe phenotypes arise. Here we describe the generation of a mouse model in which the total degradation of unsaturated fatty acids is prevented by disruption of an auxiliary enzyme of β-oxidation. Although degradation of saturated fatty acids proceeds normally, the phenotype presented here is in many ways similar to mouse models of the disrupted classical β-oxidation pathway, but with additional unique features. The null mutant mice are asymptomatic until exposed to fasting, during which they switch on ketogenesis, but simultaneously develop hypoglycemia. A number of human patients suffer from idiopathic hypoglycemia (hypoglycemia of unknown cause). Our mouse model links this disease state to a specific defect in the breakdown of polyunsaturated fatty acids. Furthermore, it shows that degradation of unsaturated fatty acids is essential for balanced fatty acid and energy metabolism, as well as adaptation to metabolic stress.