Abstract
Sir2 is an evolutionarily conserved NAD+ dependent protein. Although, SIRT1 has been implicated to be a key regulator of fat and glucose metabolism in mammals, the role of Sir2 in regulating organismal physiology, in invertebrates, is unclear. Drosophila has been used to study evolutionarily conserved nutrient sensing mechanisms, however, the molecular and metabolic pathways downstream to Sir2 (dSir2) are poorly understood. Here, we have knocked down endogenous dSir2 in a tissue specific manner using gene-switch gal4 drivers. Knockdown of dSir2 in the adult fatbody leads to deregulated fat metabolism involving altered expression of key metabolic genes. Our results highlight the role of dSir2 in mobilizing fat reserves and demonstrate that its functions in the adult fatbody are crucial for starvation survival. Further, dSir2 knockdown in the fatbody affects dilp5 (insulin-like-peptide) expression, and mediates systemic effects of insulin signaling. This report delineates the functions of dSir2 in the fatbody and muscles with systemic consequences on fat metabolism and insulin signaling. In conclusion, these findings highlight the central role that fatbody dSir2 plays in linking metabolism to organismal physiology and its importance for survival.
Highlights
Studies from different model organisms have shown that nutrient sensing factors or pathways [1, 2] such as AMP-activated kinase (AMPK) [3], insulin-IGF signaling (IIS) [4, 5], target of rapamycin (TOR) [6] and Sirtuins (Sir2-like) [7, 8] are key players in maintaining metabolic homeostasis
We found that backcrossed downstream to Sir2 (dSir2) mutant (Sir22A.7.11) flies (Supplementary Figure 1) were more sensitive to starvation when compared to the controls (Figure 1A and Supplementary Figure 2)
We report that dSir2 is a critical factor that regulates metabolic homeostasis and mediates organismal physiology (Figure 6)
Summary
Studies from different model organisms have shown that nutrient sensing factors or pathways [1, 2] such as AMP-activated kinase (AMPK) [3], insulin-IGF signaling (IIS) [4, 5], target of rapamycin (TOR) [6] and Sirtuins (Sir2-like) [7, 8] are key players in maintaining metabolic homeostasis. Sir was identified as a key determinant of longevity in Saccharomyces cerevisiae and its dependence on NAD+ for its activity is crucial for its ability to link calorie/dietary restriction (CR/DR) with lifespan extension [18, 19]. In the absence of a clear understanding of the evolutionary conservation of molecular functions of Sir in metazoans, its roles in regulating organismal physiology and survival are still not well appreciated. In this regard, studies that dissect out molecular functions of Sir will provide insights into its role in response to calorie restriction and aging
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