Accumulation of ceramide, a type of simple sphingolipid, has been associated with metabolic syndrome and obesity in humans and mice. With the goal of elucidating types of perturbations of sphingolipid metabolism that lead to obese phenotypes, mutations of Drosophila genes involved in this process have been studied. In addition to biochemical and behavioral assays, DNA microarrays have been used to detect differential gene expression. Both "lean" and obese phenotypes are observed; caloric-intake dependency has been assessed, and both intake-independent and intake-dependent phenotypes are observed.
Loss-of-function genotypes for the following genes have been assessed: lace (orthologous to human SPTLC2 and SPTLC3, required for de novo sphingolipid synthesis); ifc (orthologous to human DEGS1 and DEGS2, required for ceramide synthesis); schlank (orthologous to human CERS5, CERS6, CERS2 and other ceramide synthases); Sk2 (orthologous to human SPHK1 and SPHK2, sphingosine kinases involved in regulation of sphingosine degradation) and Sply (orthologous to human SGPL1, a sphingosine lyase involved in sphingosine degradation). Phenotypes of animals carrying selected double mutant combinations have also been characterized. Genes observed to be differentially expressed include Akh and RYa-R. In a study associating metabolic phenotypes with variants found in the Drosophila Genetic Reference Panel (DGRP) lines, Dmel\schlank was identified as having a significant metabolic role.
For a number of the orthologous human genes, including Hsap\DEGS1, Hsap\CERS6, Hsap\CERS2, and Hsap\CERS3, a construct of a tagged the wild-type gene has been introduced into flies, but none has been characterized in the context of this disease model. For Hsap\DEGS1, heterologous rescue (functional complementation) of the amorphic ifc larval lethal phenotype has been demonstrated.
[updated Apr. 2020 by FlyBase; FBrf0222196
Obesity is an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. Obesity is associated with increased risk of illness, disability, and death. (http://medical-dictionary.thefreedictionary.com/obesity).
The development of obesity is recognized as having both genetic and environmental components (https://www.sciencelearn.org.nz/resources/203-obesity-genetic-or-environmental).
Accumulation of ceramide has been associated with metabolic syndrome and obesity in humans and mice (Walls, et al., 2013, and references therein; FBrf0223736).
Ceramide is a major molecule in sphingolipid metabolism and has been studied extensively. In addition to its structural role in plasma membranes and lipoproteins, ceramide and its metabolites have profound effects on cellular signaling, such as apoptosis and insulin response (Park and Goldberg, 2012, pubmed:22999245).
Moderate- to high-scoring ortholog of human SPTLC2 and SPTLC3 (1 Drosophila to 2 human). Dmel\lace shares 50-57% identity and 68-77% similarity with the human genes.
High-scoring ortholog of human DEGS2 and DEGS1 (1 Drosophila to 2 human). Dmel\ifc shares 58-62% identity and 72-76% similarity with the human genes.
High-scoring ortholog of human CERS5 and CERS6; moderate-scoring ortholog of human CERS2, CERS3, CERS4 (1 Drosophila to 5 human). Dmel\schlank shares 38-42% identity and 59-62% similarity with the human genes.
High-scoring ortholog of human SGPL1 (1 Drosophila to 1 human). Dmel\Sply shares 50% identity and 69% similarity with the human gene.
