Intramyocellular Fatty-Acid Metabolism Plays a Critical Role in Mediating Responses to Dietary Restriction in Drosophila melanogaster

Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Cell metabolism (Impact Factor: 17.57). 07/2012; 16(1):97-103. DOI: 10.1016/j.cmet.2012.06.005
Source: PubMed


Changes in fat content have been associated with dietary restriction (DR), but whether they play a causal role in mediating various responses to DR remains unknown. We demonstrate that upon DR, Drosophila melanogaster shift their metabolism toward increasing fatty-acid synthesis and breakdown, which is required for various responses to DR. Inhibition of fatty-acid synthesis or oxidation genes specifically in the muscle tissue inhibited life-span extension upon DR. Furthermore, DR enhances spontaneous activity of flies, which was found to be dependent on the enhanced fatty-acid metabolism. This increase in activity was found to be at least partially required for the life-span extension upon DR. Overexpression of adipokinetic hormone (dAKH), the functional ortholog of glucagon, enhances fat metabolism, spontaneous activity, and life span. Together, these results suggest that enhanced fat metabolism in the muscle and physical activity play a key role in the protective effects of DR.

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    • "Male flies from either CS or w 1118 also showed a similar increase in expression of tim and per mRNA upon DR (Figure S1B). However, we have used female flies for all other experiments as they typically show a stronger response to variation of yeast in the diet (Katewa et al., 2012; Vargas et al., 2010). We also observed that a minimum of 6 days of DR treatment is required to see a robust response in clock gene amplitude (data not shown). "
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    ABSTRACT: Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass-spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging.
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    • "These data are consistent with the difference in mean survival under starvation between young and old flies (Fig. 1D) and suggest that decreased FFL in old flies is correlated with decreased fat stores. It has been reported that food shortage increases locomotor activity in young flies and this may facilitate foraging behavior (Lee & Park, 2004; Katewa et al., 2012). We measured the amount of locomotor activity in young and old CS flies under food deprivation during the time when significant difference is observed in trap entries. "
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    • "Feeding flies diets that are low in yeast can model protein-specific undernutrition and severely shorten lifespan (Bruce et al., 2013; Ja et al., 2009; Katewa et al., 2012; Zid et al., 2009). In this study, we asked whether microbial association could rescue the effect of protein deficiency. "
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