Fitzgerald, L. | bioRxiv Science

bioRxiv2026

Novel Regulators of Sugar-dependent Food Consumption in Drosophila melanogaster

Diet and genetic background interact to influence food consumption, yet the genetic basis of diet-dependent feeding behavior remains poorly understood. Here, we used genome-wide association analysis (GWAS) to investigate the genetic regulation of sugar-dependent food consumption in Drosophila melanogaster. Food intake was quantified in 176 lines of the Drosophila Genetic Reference Panel (DGRP) using the Con-Ex (Consumption-Excretion) assay on low- and high-sugar foods. Flies showed compensatory feeding, consuming more low-sugar food than high-sugar food, and this behavior was largely maintained across genotypes. Additionally, the magnitude and overall consumption varied several-fold among lines, with broad-sense heritability of 0.53 to 0.66 across sexes and diets. Association analysis across six sex- and diet-specific phenotypes identified 161 variants mapping to 118 candidate genes, which shared almost no loci between dietary conditions, indicating that consumption on the two foods is largely under separate genetic control. RNAi knockdown of candidate genes identified CG42673 and Tmtc2, whose knockdown increased consumption across sexes and diets and was reproduced in independent experiments. Together, these findings show that natural genetic variation contributes substantially to diet-dependent feeding and identify candidate regulators of sugar-based food consumption in Drosophila.

genetics↗

bioRxiv2021

Chronic Aryl Hydrocarbon Receptor Activity Phenocopies Smoking-induced Skeletal Muscle Impairment

BackgroundCOPD patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact. MethodsWe used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer). Results16 weeks tobacco smoke exposure in mice caused: muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signaling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. ConclusionsThese results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

physiology↗