Intramyocellular fatty-acid metabolism plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster.

Subhash Katewa, Fabio Demontis, Marysia Kolipinski, Alan Hubbard, Matthew Gill, Norbert Perrimon, Simon Melov and Pankaj Kapahi

Cell metabolism 2012. 16: 97-103.


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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This study focuses on the relationship between fat metabolism and the protective effects of dietary restriction. It has been shown in previous studies that flies on DR have higher triglyceride levels in their fat bodies. In addition to confirming this finding, this study showed that flies on DR have increased levels of lipogenesis and lipolysis using a technique whereby the fly food was spiked with 14C labeled glucose. They also studied the effects of dACC inhibition, a key enzyme in fat metabolism, through the use of dACC RNAi. Inhibition of dACC reversed many of the protective effects of DR, including cold-stress resistance, oxidative stress resistance, and life-span extension. These findings indicate the dACC plays an important role in mediating the DR-dependent changes in fat metabolism, stress resistance, and life span. A genome-wide transcriptional analysis was performed in order to identify the genes whose expression was altered by DR and then whose altered expression was then reversed upon dACC inhibition. The products of the identified genes are predominately involved in muscle structure and function. In order to study the tissue-specific effects of dACC inhibition, dACC was inhibited in the fat body, neurons, and muscle. The DR-dependent increase in lifespan was reduced only when dACC was inhibited in muscle.

These findings suggest that increased fat metabolism in muscle is critical for DR induced lifespan extension. This study also examined the relationship between the DR-dependent increase in muscle activity and lifespan extension. The investigators concluded that dACC inhibition reduced the protective effects of DR on age-related decline in muscle activity. This phenomenon was further studied through the use of flies with ablated wings, causing a reduction in movement. Flies with either clipped-wings or genetically ablated wings exhibited a reduction in the lifespan extension effects of DR. The paper concludes a study involving the overexpression of AKH, an ortholog of glucagon, which is involved in glucose and lipid metabolism. Flies ubiquitously overexpressing AKH showed an increase in triglyceride synthesis and breakdown and spontaneous movement, and while lifespan was extended in AL control flies, there were no further effects on the lifespan of DR flies.

Written by Izzy Hatfield on July 30, 2013.


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