Abstract
The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period01 (per01) clock mutants and Canton-S wildtype (WTCS) flies in an isogenic and non-isogenic background using LC–MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WTCS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.
Highlights
The interaction between circadian clocks and metabolism is of increasing interest, since clock dysfunction often correlates with metabolic pathologies [1] and frequent eating causes chronic disruption of the circadian clock and decreases lifespan [2]
The fruit fly, Drosophila melanogaster, provides a genetically tractable model to address the complex interplay between circadian clocks and metabolism [9]
A mutation in the clock gene period affects intermediates of storage lipid breakdown To investigate whether the circadian clock affects lipid metabolism, we first compared the lipid profile between fed clock mutant and wildtype flies
Summary
The interaction between circadian clocks and metabolism is of increasing interest, since clock dysfunction often correlates with metabolic pathologies [1] and frequent eating causes chronic disruption of the circadian clock and decreases lifespan [2]. A recent liquid chromatography–mass spectrometry (LC–MS) study on fruit fly metabolome in bodies (thorax and abdomen) of w1118 wildtype-like and per mutant flies showed oscillation in profiled polar metabolites [14]. Low-caloric food increased the amplitude and robustness of clock gene oscillations in the fat body [16] Notwithstanding this recent progress, the circadian regulation of lipid metabolism in Drosophila remains largely unexplored. As the genetic background may affect overall metabolic features, the extent to which observed differences are due to general background effects remains elusive To help filling these gaps in knowledge and to meet the need for a higher number of chronometabolomic studies [17], we compared metabolite profiles including lipids between per mutant and wildtype flies (wildtype Canton S, W TCS) in a non-isogenic and isogenic background using LC–MS-based metabolomics. In combination with increased starvation susceptibility and increased stress marker level in per mutants, our data point towards altered mitochondrial activity in flies with a perturbed clock
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