Metabolomics of the Wolfram Syndrome 1 Gene (Wfs1) Deficient Mice

Abstract

Wolfram syndrome 1 is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Mutations in the WFS1 gene encoding the wolframin glycoprotein can lead to endoplasmic reticulum stress and unfolded protein responses in cells, but the pathophysiology at whole organism level is poorly understood. In this study, several organs (heart, liver, kidneys, and pancreas) and bodily fluids (trunk blood and urine) of 2- and 6-month old Wfs1 knockout (KO), heterozygote (HZ), and wild-type (WT) mice were analyzed by untargeted and targeted metabolomics using liquid chromatography-mass spectrometry. The key findings were significant perturbations in the metabolism of pancreas and heart before the onset of related clinical signs such as glycosuria that precedes hyperglycemia and thus implies a kidney dysfunction before the onset of classical diabetic nephropathy. The glucose use and gluconeogenesis in KO mice are intensified in early stages, but later the energetic needs are mainly covered by lipolysis. Furthermore, in young mice liver and trunk blood hypouricemia, which in time turns to hyperuricemia, was detected. In summary, we show that the metabolism in Wfs1-deficient mice markedly differs from the metabolism of WT mice in many aspects and discuss the future biological and clinical relevance of these observations.

Soft drinks and monogenetic diabetes: a study on the Wolfram syndrome 1 (Wfs1) deficient mouse model

“…It has been previously shown that the KO mice consume less food when on standard diet compared to the WT littermates [27]. Additionally, it is known that the physical growth of the Wfs1 deficient mice is retarded [21] and in a recent metabolomics study we hypothesized that defective collagen synthesis for connective tissue may be a key process [16]. Reduced solid food intake and reduced capability for tissue expansion both can counter the increased calories from drink.…”

“…Increased thirst is apparent in all genotypes when drinking a sucrose solution. We have previously shown that the concentration of hexoses in the urine and kidneys of KO mice is increased compared to their WT littermates [16]. Therefore, in KO animals hyperosmolar urine excretes the excessive amount of water, meaning that even higher water intake is required to compensate for the inefficiency of the kidneys.…”

“…Caffeine is a structural analogue of uric acid. We have previously shown that uric acid metabolism is severely affected by Wfs1-deficiency [16]. Additionally, in humans, sucrose containing soft drinks have been shown to interfere with uric acid production [25,26].…”

“…Along with metabolic profiling, targeted metabolomics was carried out with selected hydroxyl acids, all proteogenic amino acids and acylcarnitines using a previously described method [16]. Acylcarnitines (free, acetyl-, propionyl-and butyrylcarnitine) were analyzed as the precursors of m/z 85 ion and all amino acids were analyzed by multiple reaction monitoring scan.…”

“…We have previously generated and characterized Wfs1-deficient mice [14][15][16]. They exhibit impaired glucose tolerance due to insufficient insulin secretion [17] and wolframin may play an important role in maintaining homeostasis in beta-cells [18,19].…”