Regulated inositol synthesis is critical for balanced metabolism and development in Drosophila melanogaster

Abstract

Myo-inositol is a precursor of the membrane phospholipid, phosphatidylinositol (PI). It is involved in many essential cellular processes including signal transduction, energy metabolism, endoplasmic reticulum stress, and osmoregulation. Inositol is synthesized from glucose-6-phosphate by myo-inositol-3-phosphate synthase (MIPSp). The Drosophila melanogaster Inos gene encodes MIPSp. Abnormalities in myo-inositol metabolism have been implicated in type 2 diabetes, cancer, and neurodegenerative disorders. Obesity and high blood (hemolymph) glucose are two hallmarks of diabetes, which can be induced in Drosophila melanogaster third-instar larvae by high-sucrose diets. This study shows that dietary inositol reduces the obese-like and high-hemolymph glucose phenotypes of third-instar larvae fed high-sucrose diets. Furthermore, this study demonstrates Inos mRNA regulation by dietary inositol; when more inositol is provided there is less Inos mRNA. Third-instar larvae with dysregulated high levels of Inos mRNA and MIPSp show dramatic reductions of the obese-like and high-hemolymph glucose phenotypes. These strains, however, also display developmental defects and pupal lethality. The few individuals that eclose die within two days with striking defects: structural alterations of the wings and legs, and heads lacking proboscises. This study is an exciting extension of the use of Drosophila melanogaster as a model organism for exploring the junction of development and metabolism.

Inositol in Disease and Development: Roles of Catabolism via myo-Inositol Oxygenase in Drosophila melanogaster

“…Adult P- miox f01770 /P- miox f01770 were not included in experiments because they are rarely viable, with only ~6% of the pupae eclosing and the flies that eclose dying within two days ( Figure 3 A). These results are similar to previously published findings that highly upregulated myo -inositol synthesis reduces eclosion to ~9% [ 17 ]. As myo- inositol is a precursor of the phosphatidylinositol phosphates (PIPs), it is interesting to note that inositol phosphate kinase 2 ( Ipk2 ) deletions and dysregulation of the expression of the phosphatidylinositol synthase gene ( Pis ) also cause pupal lethality [ 68 , 69 ].…”

“…Rats with upregulated myo- inositol catabolism have increased blood glucose and related pathobiological stress [ 13 , 14 , 15 ]. In the fruit fly, Drosophila melanogaster, reduced myo- inositol synthesis was shown to cause defective spermatogenesis [ 16 ], and increased myo- inositol synthesis caused severe developmental defects [ 17 ]. This led to the current study investigating the role of myo- inositol catabolism in fruit fly development and metabolism.…”

“…Head involution includes the rearrangement of lobes that form larval head structures, concurrent with the relocation of the imaginal disc primordia that later contribute to adult head structures, including the proboscis [ 57 , 58 ]. Rivera et al [ 17 ] demonstrated that dietary myo- inositol and/or increasing myo- inositol synthesis via genetic manipulation alleviated obesity and high-hemolymph glucose; however, extremely high levels of constitutive myo- inositol synthesis resulted in pupal lethality and developmental defects (lacking proboscises and with structural alterations of the legs and wings).…”

Inositol supplementation - known and possible applications

“…Kolejne próby otrzymania tego cyklicznego alkoholu opierały się na izolacji związku z liści roślin oraz eukariotycznych i prokariotycznych tkanek [1]. Związek ten jest prekursorem fosfolipidu błonowego fosfatydyloinozytolu i w organizmie wytwarzany jest z glukozo-6fosforanu przez syntazę mio-inozytol-3-fosforanu [2]. Występuje on w 9 formach izomerycznych, lecz jego izomery mioinozytol oraz D-chiro-inozytol zyskały duże zainteresowanie badaczy ze względu na wywieranie wielu pozytywnych efektów zdrowotnych.…”

Obesity and Cancer: Potential Mediation by Dysregulated Dietary Phosphate

“…Dysregulated PKCβ is common in many cancers and may be implicated in cancer development. Additionally, dysregulated inositol synthesis in Drosophila melanogaster fed a high-sucrose diet is a potential model for similar inositol abnormalities in human cancer and obesity [8]. However, few research studies have investigated dysregulated endocrine metabolism of dietary phosphate as a potential mediating factor in the association of obesity with cancer.…”