Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

Abstract

Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.T O attain proper cellular growth, availability of nutrients is imperative, because the nutrient supply fuels energy metabolism. Thus lack of nourishment cause limited growth of the organism due to reduced energy metabolism (Hietakangas and Cohen 2009;DePalma et al. 2012). Sensing and transport of growth signals happen in two distinct pathways: at the cellular level, the TOR pathway governs growth (Saltiel and Kahn 2001;Grewal 2009), whereas insulin signaling is responsible for subsequent adjustment of the cellular metabolism causing growth at a more systemic level. Ultimate convergence of these two signaling pathways leads to balanced growth. Therefore each member of the insulin-TOR pathway has recognized influence on cell size and cell growth as demonstrated either in cell clones or at the whole organism level. Severe growth defect during prenatal development such as intrauterine growth restriction and low birth weight have been linked to paucity of insulinTor signaling (Murakami et al. 2004;Gannage-Yared et al. 2012) and ATP production (Selak et al. 2003). Like in most animals, the insulin-TOR signaling pathway in Drosophila is dedicated to the control of growth and metabolism ( Figure 1A). With its enriched genetic and genomic resources, flies have contributed significantly toward the understanding of nutritional physiology and ce...

PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase

“…In a recent report TOR signaling was found to function as a positive regulator of PGC-1/ srl in growth process during larval development of Drosophila (Mukherjee and Duttaroy, 2013), which is consistent with previous findings that PGC-1/ srl -deficient Drosophila larvae exhibit dramatic growth impairment (Tiefenbock et al, 2010). In contrast, however, we provided strong evidence in this study that during metabolic homeostasis in the adult animal, PGC-1/ srl is a negative effector of HFD-induced augmentation of TOR signaling.…”

A role for triglyceride lipase brummer in the regulation of sex differences in Drosophila fat storage and breakdown

“…Future studies will therefore be important to confirm whether the sex-specific regulation of bmm mRNA under normal culture conditions and post-starvation occurs via IIS and Foxo. Furthermore, it will be important to test whether additional nutrient-responsive pathways contribute to the sex-specific regulation of bmm and the male-female difference in triglyceride storage, such as the adipokinetic hormone (AKH; FBgn0004552) pathway [68,83,84], the sterol response element binding protein (SREBP; FBgn0261283) pathway [85,86], and spargel/peroxisome proliferator-activated receptor γ coactivator 1 (srl/PGC-1; FBgn0037248) pathway [87,88], as much of our knowledge of these pathways is derived from studies using either a mixed-sex population of larvae or adult male flies. Another possible explanation for the sex differences in triglyceride homeostasis is that sex determination genes directly establish a "male" or a "female" metabolic state via regulation of triglyceride metabolism genes such as bmm.…”

Emerging functional similarities and divergences between Drosophila Spargel/dPGC-1 and mammalian PGC-1 protein

“…We recently demonstrated that a Spargel-GFP fusion protein also localizes itself in the nucleus forming distinct punctate structures (Mukherjee and Duttaroy, 2013). An authentic Nuclear Localization Signal (NLS) was uncovered in Spargel/dPGC-1 with the help of a NLS predict software (Mukherjee and Duttaroy, 2013) that most likely assists in Spargel/dPGC-1 localization into the nucleus.…”

“…Spargel/dPGC-1 is a terminal effector of this pathway hence reduced spargel expression results in growth retardation with smaller body size and developmental delays, though Spargel/dPGC-1 overexpression has no immediate effect on growth (Rera et al, 2011; Mukherjee and Duttaroy, 2013). …”