Endocrine and physiological regulation of neutral fat storage in Drosophila

doi:10.1016/j.mce.2017.09.008

Molecular and Cellular Endocrinology

Volume 461, 5 February 2018, Pages 165-177

https://doi.org/10.1016/j.mce.2017.09.008 Get rights and content

Highlights

•
Similar signaling processes govern fat store regulation in flies and mammals.
•
Genetic screens in Drosophila discover new regulators of body fat depots.
•
Drosophila genetics gauges the biological importance of fat store regulators.

Abstract

After having revolutionized our understanding of the mechanisms of animal development, Drosophila melanogaster has more recently emerged as an equally valid genetic model in the field of animal metabolism. An increasing number of studies have revealed that many signaling pathways that control metabolism in mammals, including pathways controlled by nutrients (insulin, TOR), steroid hormone, glucagon, and hedgehog, are functionally conserved between mammals and Drosophila. In fact, genetic screens and analyses in Drosophila have identified new players and filled in gaps in the signaling networks that control metabolism. This review focuses on data that show how these networks control the formation and breakdown of triacylglycerol energy stores in the fat tissue of Drosophila.

Introduction

Organisms are highly ordered structures that can only assemble and maintain themselves through processes that require energy. How organisms harness sources of energy is one of the fundamental questions in biology. This question has gained additional importance by the growing obesity pandemic among human populations (Ng et al., 2014). The excessive accumulation of body fat in the obese is associated with metabolic dysregulation that manifests itself as type II diabetes and that can lead to cancer, cardiovascular disease and other health problems (Bastien et al., 2014, Gallagher and LeRoith, 2010, Seidell, 2000). Efforts to curb the obesity pandemic will be critically informed by basic research into the fundamental principles of fat metabolism. Much of this basic research is done in humans and mammalian models. However, in recent years it has become evident that the fruit fly Drosophila melanogaster, a simple genetic model organism, is uniquely situated to uncover basal causal relationships between adiposity and metabolic changes on a physiological level. Fruit flies will become obese under certain dietary conditions and obese flies show signs of diabetes, exhibit insulin resistance, and have impaired cardiac function. These studies have established Drosophila as a model for obesity studies and are discussed in several excellent recent reviews (Baker and Thummel, 2007, Diop and Bodmer, 2015, Graham and Pick, 2017, Kühnlein, 2011, Owusu-Ansah and Perrimon, 2014). Here, I will first briefly review anabolic and catabolic pathways that determine the size of storage fat depots in Drosophila (for an in-depth review, see Kühnlein, 2012). The main focus of this review, however, will be on pathways and mechanisms that control the formation and breakdown of fat stores in Drosophila.

Section snippets

Fat storage and transport in Drosophila

Animals use neutral fats or triacylglycerols (TAGs) to store chemical energy that is not immediately needed for the maintenance of normal cellular and organismal functions. As fatty acid esters of glycerol, TAGs are energy-dense and highly hydrophobic, forming compact energy stores in the form of cytoplasmic lipid droplets. In recent years it has become clear that lipid droplets not only serve as energy stores, but are dynamic cell organelles that have a variety of other cellular functions and

The de novo synthesis of neutral fats

Neutral fats are derived from two basic building blocks, glycerol-3 phosphate and fatty acids. If not derived from nutritional sources or the breakdown of stored fat, fatty acids can be synthesized de novo from acetyl-CoA that is derived from the breakdown of carbohydrates and proteins. De novo synthesis of neutral fats occurs through the glycerol-3-phosphate pathway, which converts glycerol-3-phosphate into TAG by esterification with fatty acids in 4 enzymatic steps (Fig. 1A). The last step in

The breakdown of neutral fats

The synthesis of fat is balanced by its breakdown, which is carried out by lipases in both mammals and Drosophila. Drosophila has two lipases that have been shown to contribute to lipolysis, the adipocyte triglyceride lipase (ATGL) homolog Brummer (BMM) and the hormone-sensitive lipase homolog HSL (Bi et al., 2012, Gronke et al., 2005). Additional putative lipases await characterization (Horne et al., 2009), among them lipases encoded by CG 1882, CG5966 and the brummer-like dob gene. All three

Overview of insulin and TOR pathways

How does the availability of nutrients drive lipogenesis and lipolysis? Two major signaling pathways that mediate the effects of nutrients are the insulin and TOR (target of rapamycin) pathways. In both mammals and Drosophila, the effects of insulin or insulin-like peptides are mediated by an insulin receptor that activates a signaling axis consisting of the phosphatidylinositol 3-kinase PI3K and the protein kinase Akt (aka protein kinase B) (Manning and Toker, 2017). In mammals, the same axis

Concluding remarks

The power of the established toolset of genetic analysis in Drosophila together with newly emerging techniques such as CRISPR/Cas9 mutagenesis ensures that Drosophila will continue to make seminal contributions to our understanding of metabolic regulation. We have only begun to appreciate the complexity of regulatory networks that govern the control of body fat depots. For instance, it has been estimated that more than 60% of all protein-encoding genes in humans are subject to control by

Acknowledgements

I am grateful to an anonymous reviewer for making excellent suggestions for improving this review, and I am grateful to Stephanie E. Hood for critical reading of the manuscript. Work in the author's laboratory is supported by the National Institutes of Health [grant number 1R15DK114748-01] and the Arkansas Biosciences Institute.

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View full text

Endocrine and physiological regulation of neutral fat storage in Drosophila

Highlights

Abstract

Introduction

Section snippets

Fat storage and transport in Drosophila

The de novo synthesis of neutral fats

The breakdown of neutral fats

Overview of insulin and TOR pathways

Concluding remarks

Acknowledgements

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Arch. Biochem. Biophys.

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Prog. Cardiovasc. Dis.

Cell Metab.

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Cell Metab.

Insect biochem. Mol. Biol.

Cell

Curr. Biol.

J. Lipid Res.

Sem. Cell Dev. Biol.

Curr. Biol.

Cell

Curr. Top. Dev. Biol.

Trends Endocrinol. Metab

Mol. Cell

Cell Metab.

Curr. Top. Dev. Biol.

Curr. Biol.

Cell Metab.

J. Biol. Chem.

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Insect biochem. Mol. Biol.

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Biochem. Biophys. Res. Commun.

Mol. Metab.

Cell Rep.

Cell Metab.

J. Lipid Res.

Prog. Lipid Res.

Cell Metab.

Dev. Cell

J. Lipid Res.

Cell Metab.

Cell

J. Biol. Chem.

Prog. Neurobiol.

Lancet

Trends Cell Biol.

Cell Metab.

Insect fat body: energy, metabolism, and regulation

Annu. Rev. Entomol.

Opposite and redundant roles of the two Drosophila perilipins in lipid mobilization

J. Cell Sci.

PhosphoPep—a database of protein phosphorylation sites in model organisms

Nat. Biotechnol.

Large clusters of co-expressed genes in the Drosophila genome

Nature

Hormonal and genetic regulation of vitellogenesis in Drosophila

Q. Rev. Biol.

Improvement of phosphoproteome analyses using FAIMS and decision tree fragmentation. application to the insulin signaling pathway in Drosophila melanogaster S2 cells

J. Proteome Res.