Regulation of Fat Cell Mass by Insulin in Drosophila melanogaster

Abstract

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 recent epidemic of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) has renewed interest in fundamental principles of metabolic homeostasis. Much attention has been directed to the appropriate control of carbohydrate metabolism, as elevated glucose is the cardinal, defining sign of diabetes mellitus. Nonetheless, an integrated and finely tuned balance of lipid storage and breakdown is also essential for metabolic well-being. Defects in lipid metabolism not only contribute directly to a number of diseases, such as the inherited lipodystrophies, the metabolic syndrome, and atherosclerosis, but also are an integral component of T2DM. In fact, it has been argued persuasively that T2DM is regarded as a disorder of glucose metabolism for purely historical reasons and that lipid abnormalities are as or more important to the pathogenesis and consequences of the disease (33). Thus, a refined, mechanistic understanding of the normal control of lipid storage and mobilization is critical.The major regulators of lipid synthesis and breakdown are glucose and the peptide hormone insulin. It is now clear that insulin signals through a canonical pathway that is phylogenetically conserved, controlling growth, development, and ageing in invertebrates (Caenorhabditis elegans and Drosophila melanogaster) and metabolic outputs in vertebrates (rodents and humans) (17, 37). For example, in mammals, insulin regulates hepatic, muscle, and adipocyte glucose metabolism in a manner dependent on signaling through phosphatidylinositol 3-kinase (PI3K) and its downstream intermediary, Akt, also known as protein kinase B (12, 44). This same pathway has also been implicated in ...

Role of Fat Body Lipogenesis in Protection against the Effects of Caloric Overload in Drosophila

“…TFA and NEFA concentrations were determined by quantitative GC using a flame ionization detector relative to a known amount of C17:0 internal standard fatty acid added to the sample prior to processing (23). We calculated the lipid derived from dietary sugar by multiplying the FA 13 C percent enrichment (Fig. 1, C and D) and the FA pool size (Table 1) for each condition.…”

“…1, C and D) and the FA pool size (Table 1) for each condition. This product was then divided by the 13 C atom percent enrichment in the tracer food (Fig. 1E) as extrapolated from the trehalose labeling.…”

“…Isotopomer distributions of labeled glucose and trehalose were measured by GC/MS on trimethylsilyl derivatives. All GC/MS isotopic enrichments were corrected for the natural abundance of 13 C in larvae prior to the consumption of tracer diets. The total atom percent excess 13 C content within TFA and NEFA was estimated from the measured fatty acid distribution profile and the total atom percent excess 13 C for each fatty acid species calculated from the distribution of labeled isotopomers.…”

“…We hypothesized that in the face of chronic exposure to HSD this storage capacity is limiting, leading to altered processing of dietary carbon and the model T2D phenotypes. To determine how HSD feeding alters carbon flux, we undertook a novel approach using stable isotope tracer methodology with uniformly 13 C-labeled glucose to study the partitioning of carbons from dietary glucose ([U- 13 C 6 ]glucose). Flies were fed diets in which [U- 13 C 6 ]glucose made up 10% of the total added glucose content.…”

“…The FB is the animal's primary fat storage depot as well as the source of antimicrobial peptides, endocrine mediators of neuronal function, and cytochrome p450 enzymes that catalyze detoxification and biosynthetic reactions (9 -12). FB insulin and adipokinetic hormone (glucagon ortholog) signaling can control lipid storage in a manner similar to that in human liver (13,14). Therefore, we studied the role of the Drosophila FB in the response to an HSD.…”