The Central Clock Neurons Regulate Lipid Storage in Drosophila

A proper balance of lipid breakdown and synthesis is essential for achieving energy homeostasis as alterations in either of these processes can lead to pathological states such as obesity. The regulation of lipid metabolism is quite complex with multiple signals integrated to control overall triglyceride levels in metabolic tissues. Based upon studies demonstrating effects of the circadian clock on metabolism, we sought to determine if the central clock cells in the Drosophila brain contribute to lipid levels in the fat body, the main nutrient storage organ of the fly. Here, we show that altering the function of the Drosophila central clock neurons leads to an increase in fat body triglycerides. We also show that although triglyceride levels are not affected by age, they are increased by expression of the amyloid-beta protein in central clock neurons. The effect on lipid storage seems to be independent of circadian clock output as changes in triglycerides are not always observed in genetic manipulations that result in altered locomotor rhythms. These data demonstrate that the activity of the central clock neurons is necessary for proper lipid storage

Student Attitudes Contribute to the Effectiveness of a Genomics CURE

The Genomics Education Partnership (GEP) engages students in a course-based undergraduate research experience (CURE). To better understand the student attributes that support success in this CURE, we asked students about their attitudes using previously published scales that measure epistemic beliefs about work and science, interest in science, and grit. We found, in general, that the attitudes students bring with them into the classroom contribute to two outcome measures, namely, learning as assessed by a pre- and postquiz and perceived self-reported benefits. While the GEP CURE produces positive outcomes overall, the students with more positive attitudes toward science, particularly with respect to epistemic beliefs, showed greater gains. The findings indicate the importance of a student\u27s epistemic beliefs to achieving positive learning outcomes

A Central Support System Can Facilitate Implementation and Sustainability of a Classroom-Based Undergraduate Research Experience (CURE) in Genomics

There have been numerous calls to engage students in science as science is done. A survey of 90-plus faculty members explores barriers and incentives when developing a research-based genomics course. The results indicate that a central core supporting a national experiment can help overcome local obstacles

A central support system can facilitate implementation and sustainability of a Classroom-based Undergraduate Research Experience (CURE) in Genomics

In their 2012 report, the President\u27s Council of Advisors on Science and Technology advocated replacing standard science laboratory courses with discovery-based research courses -a challenging proposition that presents practical and pedagogical difficulties. In this paper, we describe our collective experiences working with the Genomics Education Partnership, a nationwide faculty consortium that aims to provide undergraduates with a research experience in genomics through a scheduled course (a classroom-based undergraduate research experience, or CURE). We examine the common barriers encountered in implementing a CURE, program elements of most value to faculty, ways in which a shared core support system can help, and the incentives for and rewards of establishing a CURE on our diverse campuses. While some of the barriers and rewards are specific to a research project utilizing a genomics approach, other lessons learned should be broadly applicable. We find that a central system that supports a shared investigation can mitigate some shortfalls in campus infrastructure (such as time for new curriculum development, availability of IT services) and provides collegial support for change. Our findings should be useful for designing similar supportive programs to facilitate change in the way we teach science for undergraduates

A course-based research experience: how benefits change with increased investment in instructional time

There is widespread agreement that science, technology, engineering, and mathematics programs should provide undergraduates with research experience. Practical issues and limited resources, however, make this a challenge. We have developed a bioinformatics project that provides a course-based research experience for students at a diverse group of schools and offers the opportunity to tailor this experience to local curriculum and institution-specific student needs. We assessed both attitude and knowledge gains, looking for insights into how students respond given this wide range of curricular and institutional variables. While different approaches all appear to result in learning gains, we find that a significant investment of course time is required to enable students to show gains commensurate to a summer research experience. An alumni survey revealed that time spent on a research project is also a significant factor in the value former students assign to the experience one or more years later. We conclude: 1) implementation of a bioinformatics project within the biology curriculum provides a mechanism for successfully engaging large numbers of students in undergraduate research; 2) benefits to students are achievable at a wide variety of academic institutions; and 3) successful implementation of course-based research experiences requires significant investment of instructional time for students to gain full benefit

Allocating energy utilization for growth and metabolism: The interplay between insulin and inflammatory signaling in Drosophila melanogaster

When presented with a nutrient rich environment, an organism utilizes those energy stores for growth as well as long-term storage. However, when nutrients are no longer available or the animal encounters a stressful situation such as an infection, an organism must be able to sense a change in its environment and redirect its energy utilization to accommodate the stressful conditions. My thesis research uses the genetically tractable organism, Drosophila melanogaster, to understand the genes and pathways responsible for growth and triglyceride storage in response to nutrient abundance as well as those directing the shift in ATP utilization away from energy-consuming processes in response to various stresses such as starvation and infection. I have focused on the evolutionarily conserved insulin signaling pathway due to its known role of regulating cell and organ growth as well as glucose and lipid metabolism in a number of organisms. I have found that activating insulin signaling in the fly\u27s main triglyceride storage organ, the fat body, promotes the energy-consuming process of storing nutrients by increasing both fat cell number and cellular fat content. Conversely, when activating inflammatory signaling in the fly genetically or by infection, I have found that insulin signaling activity is decreased resulting in blunted triglyceride storage and small flies. These data suggest that the insulin signaling pathway is a central regulator of growth and metabolism and altering the activity of this pathway can shift energy utilization away from energy-consuming processes during times of stress

Allocating energy utilization for growth and metabolism: The interplay between insulin and inflammatory signaling in Drosophila melanogaster

When presented with a nutrient rich environment, an organism utilizes those energy stores for growth as well as long-term storage. However, when nutrients are no longer available or the animal encounters a stressful situation such as an infection, an organism must be able to sense a change in its environment and redirect its energy utilization to accommodate the stressful conditions. My thesis research uses the genetically tractable organism, Drosophila melanogaster, to understand the genes and pathways responsible for growth and triglyceride storage in response to nutrient abundance as well as those directing the shift in ATP utilization away from energy-consuming processes in response to various stresses such as starvation and infection. I have focused on the evolutionarily conserved insulin signaling pathway due to its known role of regulating cell and organ growth as well as glucose and lipid metabolism in a number of organisms. I have found that activating insulin signaling in the fly\u27s main triglyceride storage organ, the fat body, promotes the energy-consuming process of storing nutrients by increasing both fat cell number and cellular fat content. Conversely, when activating inflammatory signaling in the fly genetically or by infection, I have found that insulin signaling activity is decreased resulting in blunted triglyceride storage and small flies. These data suggest that the insulin signaling pathway is a central regulator of growth and metabolism and altering the activity of this pathway can shift energy utilization away from energy-consuming processes during times of stress

Regulation of Fat Cell Mass by Insulin in Drosophila melanogaster▿

A phylogenetically conserved response to nutritional abundance is an increase in insulin signaling, which initiates a set of biological responses dependent on the species. Consequences of augmented insulin signaling include developmental progression, cell and organ growth, and the storage of carbohydrates and lipids. Here, we address the evolutionary origins of insulin's positive effects on anabolic lipid metabolism by selectively modulating insulin signaling in the fat body of the fruit fly, Drosophila melanogaster. Analogous to the actions of insulin in higher vertebrates, those in Drosophila include expansion of the insect fat cell mass both by increasing the adipocyte number and by promoting lipid accumulation. The ability of insulin to accomplish the former depends on its capacity to bring about phosphorylation and inhibition of the transcription factor Drosophila FOXO (dFOXO) and the serine/threonine protein kinase shaggy, the fly ortholog of glycogen synthase kinase 3 (GSK3). Increasing the amount of triglyceride per cell also depends on the phosphorylation of shaggy but is independent of dFOXO. Thus, the findings of this study provide evidence that the control of fat mass by insulin is a conserved process and place dFOXO and shaggy/GSK3 downstream of the insulin receptor in controlling adipocyte cell number and triglyceride storage, respectively

The regulation of carnitine palmitoyltransferase 1 (CPT1) mRNA splicing by nutrient availability in Drosophila fat tissue

After a meal, excess nutrients are stored within adipose tissue as triglycerides in lipid droplets. Previous genome-wide RNAi screens in Drosophila cells have identified mRNA splicing factors as being important for lipid droplet formation. Our lab has previously shown that a class of mRNA splicing factors called serine/arginine-rich (SR) proteins, which help to identify intron/exon borders, are important for triglyceride storage in Drosophila fat tissue, partially by regulating the splicing of the gene for carnitine palmitoyltransferase 1 (CPT1), an enzyme important for mitochondrial β-oxidation of fatty acids. The CPT1 gene in Drosophila generates two major isoforms, with transcripts that include exon 6A producing more active enzymes than ones made from transcripts containing exon 6B; however, whether nutrient availability regulates CPT1 splicing in fly fat tissue is not known. During ad libitum feeding, control flies produce more CPT1 transcripts containing exon 6B while fasting for 24 h results in a shift in CPT1 splicing to generate more transcripts containing exon 6A. The SR protein 9G8 is necessary for regulating nutrient responsive CPT1 splicing as decreasing 9G8 levels in fly fat tissue blocks the accumulation of CPT1 transcripts including exon 6A during starvation. Protein kinase A (PKA), a mediator of starvation-induced lipid breakdown, also regulates CPT1 splicing during starvation as transcripts including exon 6A did not accumulate when PKA was inhibited during starvation. Together, these results indicate that CPT1 splicing in adipose tissue responds to changes in nutrient availability contributing to the overall control of lipid homeostasis

The ESCRT-III Protein Chmp1 Regulates Lipid Storage in the Drosophila Fat Body

Defects in how excess nutrients are stored as triglycerides can result in several diseases including obesity, heart disease, and diabetes. Understanding the genes responsible for normal lipid homeostasis will help understand the pathogenesis of these diseases. RNAi screens performed in Drosophila cells identified genes involved in vesicle formation and protein sorting as important for the formation of lipid droplets; however, all of the vesicular trafficking proteins that regulate lipid storage are unknown. Here, we characterize the function of the Drosophila Charged multivesicular protein 1 (Chmp1) gene in regulating fat storage. Chmp1 is a member of the ESCRT-III complex that targets membrane localized signaling receptors to intralumenal vesicles in the multivesicular body of the endosome and then ultimately to the lysosome for degradation. When Chmp1 levels are decreased specifically in the fly fat body, triglyceride accumulates while fat-body-specific Chmp1 overexpression decreases triglycerides. Chmp1 controls triglyceride storage by regulating the number and size of fat body cells produced and not by altering food consumption or lipid metabolic enzyme gene expression. Together, these data uncover a novel function for Chmp1 in controlling lipid storage in Drosophila and supports the role of the endomembrane system in regulating metabolic homeostasis