dSir2 deficiency in the fatbody, but not muscles, affects systemic insulin signaling, fat mobilization and starvation survival in flies

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.

Fat Body dSir2 Regulates Muscle Mitochondrial Physiology and Energy Homeostasis Nonautonomously and Mimics the Autonomous Functions of dSir2 in Muscles

“…We have earlier shown that ablating dSir2 in the fat body results in defective fat metabolism (5). In this study, we have found that fat body dSir2-mediated changes affect lipid homeostasis, influence dilp production in the IPCs, and lead to an increase in insulin signaling in the fat body (Fig.…”

“…Aberrations in mitochondrial functions are often associated with impaired insulin signaling. Our previous work shows that dSir2 affects insulin signaling by regulating the expression of the Drosophila insulin-like peptides (dILP2 and -5 and not the other dILPs) in a diet-dependent manner (5). To investigate if the altered mitochondrial functions observed in the results shown in Fig.…”

“…We have earlier shown that fat body dSir2 regulates systemic insulin signaling and affects fat metabolism (5). To determine if the aberrations in insulin signaling arose due to defects in fat metabolism, we looked at triglyceride levels, phospho-AKT levels, and expression of insulin signaling components in the fat body of fbdSir2 KD flies.…”

“…Recent reports in mammals and flies clearly show that SIRT1/ Sir2 plays an important role in fat metabolism (5)(6)(7)(8)(9)(10)(11)(12) and affects starvation survival (5). Additionally, ablation of SIRT1 in liver and muscles has been shown to result in an insulin resistance-like phenotype (12,13).…”

Dietary Supplementation of Citric acid (monohydrate) Improves Health Span in Drosophila melanogaster

“…This was done according to the method described in [25]. For this, fat body cells from third instar Drosophila larvae were dissected out in 1X PBS (pH 7.4), fixed in 4% para-formaldehyde for 20 min at room temperature and washed twice with 1X PBS.…”