Academic journal article Genetics

Regulation of Carbohydrate Energy Metabolism in Drosophila Melanogaster

Academic journal article Genetics

Regulation of Carbohydrate Energy Metabolism in Drosophila Melanogaster

Article excerpt

Preface

CARBOHYDRATE metabolism is essential for all life, having profound implications for growth, reproduction, and organismal maintenance. As multicellular animals eat periodically and experience times of starvation, carbohydrate intake can undergo extreme fluctuations. Moreover, different cell types and developmental stages have their own metabolic requirements, which, together with the changing nutrient intake, pose the need for constant regulation of carbohydrate metabolism. Therefore, complex regulatory systems have evolved to integrate these functions. In recent years, Drosophila melanogaster (hereafter Drosophila) has been increasingly utilized to study the regulation of carbohydrate metabolism and new research fields have emerged around this topic. New insight has been gained into the regulatory pathways that respond to changes in carbohydrate intake and regulate metabolism to maintain homeostasis. These include gene regulatory networks and signaling pathways, which act locally in metabolically active peripheral tissues, as well as hormonal signals, which maintain organismal homeostasis through interorgan communication. Interesting cross-talk between carbohydrate metabolism and other physiological processes, such as circadian regulation and developmental transitions, have also been uncovered. Moreover, powerful Drosophila models to study carbohydrate metabolism-related human diseases have been established. The success of Drosophila research on providing new insights into carbohydrate metabolism has its foundation in the strengths of this model system. These include a high degree of conservation of the pathways controlling carbohydrate metabolism, the ease of using simple dietary schemes, which allow studies on interactions between genes and individual nutrients, as well as a powerful genetic toolkit, which is particularly advantageous in studies that address hormonal signaling between tissues. Here, we have highlighted the recent advances in Drosophila research on carbohydrate energy metabolism. For the sake of focus, we have excluded or only touched minimally upon some related themes, such as gustatory responses, the regulation of feeding behavior, lipid metabolism, and growth control.

Part I

Homeostatic control of carbohydrate metabolism through intracellular nutrient sensing

Carbohydrate-responsive gene regulation and signaling: Fluctuations in nutrient intake pose constant requirements for homeostatic control of carbohydrate metabolism. Such regulation requires that cells are able to detect the levels of key carbohydrate-derived metabolites and consequently adjust the activity of regulatory pathways. An important layer of local regulation of carbohydrate homeostasis is mediated through so-called intracellular sugar sensing by a heterodimer of conserved basic helix-loop-helix transcription factors Mondo and Max-like protein X (Mlx, Bigmax) (Havula and Hietakangas 2012). In Drosophila larvae, Mondo-Mlx control the majority of the strongly sugar-responsive genes (Mattila et al. 2015).

Vertebrates have two Mondo paralogs, called MondoA (MLXIP) and ChREBP (Carbohydrate Response ElementBinding Protein, also known as MondoB, MLXIPL), both of which dimerize with Mlx (Havula and Hietakangas 2012). Studies in mammals have shown that the nuclear translocation and transcriptional activity of ChREBP/MondoA-Mlx are induced by glucose. The N-terminus of ChREBP and MondoA contains a so-called Glucose-Sensing-Module (GSM), which includes the low glucose inhibitory domain (LID) and the Glucose-Response Activation Conserved Element (GRACE), both of which are required for glucose sensing (Havula and Hietakangas 2012). It has been proposed that the GSM of the Mondo proteins contains a conserved motif, which resembles the glucose-6-phosphate (G-6-P)-binding site of metabolic enzymes. The binding of G-6-P to the GSM would prevent the intramolecular inhibition of GRACE imposed by LID (McFerrin and Atchley 2012). …

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