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    2019-11-06

    This research was funded by grants from the National Institute on Aging (2R01AG017141-06A2) and the National Center for Complementary and Alternative Medicine (P01AT002034). We also acknowledge the facilities service core of the Environmental Health Science Center (NIEHS ES00240). The authors would like to thank Dr. Bruce Ames (Children\'s Hospital Oakland Research Institute; Oakland, CA) for carnitine analysis, and also Dr. Viviana Pérez and Ms. Judy A. Butler for critical reading of the manuscript.
    Introduction As animals consume food, excess nutrients are stored as triglycerides mainly within adipose tissue in structures known as lipid droplets. Such storage is the result of an evolutionary MK0752 that allowed species to endure famines and plagues. As food becomes easily accessible in today\'s society and people lead sedentary lifestyles, negative consequences of overconsumption and excess nutrient storage are becoming increasingly apparent. In the United States, excessive fat storage has resulted in complications that account for some of the leading causes of death such as heart disease and stroke [1], with rates of childhood and adult obesity on the rise [2]. Understanding the biology that controls how our bodies metabolize and store excess nutrients can help both combat the increasing rates of obesity and prevent obesity-related diseases such as diabetes and cardiovascular disease. Drosophila are organisms with modest dietary and spatial needs, they have a short generation time, and can be propagated at a fairly low cost [3]. Drosophila have a simple nervous system, and store triglycerides and glycogen in a liver and adipose-like organ (called the fat body), both of which share functional similarities to those of humans. The genes regulating glycogen and lipid storage in these organs within Drosophila are highly analogous to those of humans, coding for proteins such as insulin, glucagon, and lipases [4]. Due to all of these similarities, Drosophila provide an ideal system to study the molecular control of energy metabolism, more specifically how fat storage is regulated within their fat body. In order to better understand genes important for triglyceride storage in Drosophila, genome-wide RNA interference (RNAi) screens have been performed and identified genes which, when disrupted, lead to alterations in lipid droplet size and/or number [5], [6]. One interesting family of genes, which resulted in smaller, more dispersed lipid droplets when their expression is decreased, included genes involved in RNA processing. However, whether these RNA processing genes regulated lipid storage in vivo was not known. To further understand the function of these genes in regulating lipid storage in vivo, we have decreased the expression of a number of splicing proteins specifically in the fly fat body and measured triglycerides. In addition to identifying members of the U1 and U2 snRNP as being important for lipid storage, we also identified an SR protein called 9G8/SFRS7 that is important for triglyceride storage in the Drosophila fat body [7]. This phenotype can be explained by altered splicing of a lipid metabolic gene important for β-oxidation of fatty acids known as CPT1. In Drosophila, the CPT1 gene has two isoforms resulting from a mutually exclusive alternate sixth exon (exon 6A or 6B). The product of isoforms containing exon 6A exhibits higher enzyme activity than those containing exon 6B, leading to increased lipid breakdown [8]. Interestingly, while wildtype flies had more CPT1 that included exon 6A, flies with decreased fat body 9G8 expressed higher levels of the CPT1 isoform containing exon 6B [7]. The presence of more exon 6B-containing CPT1 isoforms results in less CPT1 enzyme activity, which is consistent with the augmented triglyceride stores observed in these flies. Identifying the metabolic functions of 9G8 raised the question as to whether other RNA splicing proteins were involved in the regulation of fat metabolism. Previous studies have shown that 9G8 binds to two RNA-binding proteins called transformer (tra) and transformer2 (tra2) to correctly process the doublesex (dsx) gene, which is important for controlling sex determination [9]. While tra and tra2 have been well characterized in the regulation of sex determination, any function of these proteins in controlling metabolism is unknown.