Cardiac function and ECM morphology are altered with high fat diets inDrosophila

Abstract

Cardiovascular disease is characterized by aberrant and excessive extracellular matrix (ECM) remodelling, termed fibrosis. Fibrotic remodelling is typically triggered by inflammation, which occurs systemically in obesity. Despite the contribution of fibrosis to adverse clinical outcomes and disease progression, there are no available treatments for this condition. Developing therapeutics for chronic conditions requires an understanding ofin vivoECM regulation, and how the ECM responds to a systemic challenge. We have therefore developed aDrosophilamodel for obesity via chronic high fat diet feeding and evaluated the response of the cardiac ECM to this metabolic challenge. We found that this model displays a striking disorganization of the cardiac ECM, with corresponding deficits in heart function. Our study shows that different genotypes tolerate varying levels of high fat diets, and that some genotypes may require a different percentage of fat supplementation for achieving an optimal obesity phenotype.

Matrisome gene expression is altered during non-allometric heart growth in genetically enlargedDrosophila

“…Characterization of this overgrowth phenotype revealed that giant larvae grow to immense sizes without exhibiting hallmarks of obesity, including low triglyceride levels, reduced lipid droplet size, and gene expression reflecting an increase in mobilization of stored lipids, as well as decreased lipogenesis (Beller et al 2010; Hehlert et al 2019). This is in contrast to previous studies that have demonstrated obesity symptoms in response to high fat diet treatments (Birse et al 2010; Guida et al 2019; Andrews et al 2023). This indicates that giant larvae attain their size by overgrowth, not fat storage.…”

“…Triglyceride (TG) levels however were significantly lower in both male and female giant larvae ( Figure 1C) . Elevated TG levels have previously been noted in response to high fat diet (HFD) treatments that result in obesity phenotypes (Birse et al 2010; Guida et al 2019; Andrews et al 2023). We investigated further by labelling lipid droplets ( Figure 1D ) within the fat body and quantifying their diameter.…”

“…The appearance of the matrix was similar in giants ( Figure 2C-C’ ). We previously reported defects in matrix organization with high fat diet treatments (Andrews et al 2023), so we sought to determine if there were any organizational defects detectable in our overgrowth model. To quantify the organization of the Pericardin fibrils we utilized the Fiji macro TWOMBLI to determine the degree of alignment of fibres within the matrix.…”

“…We also quantified expression of some genes involved in fat metabolism to determine if giants are metabolically affected by their increased body size. We compared giant larvae to wandering third instar parental controls, as well as to y 1 w 1118 high fat diet (HFD) treated wandering third instars (Andrews et al 2023). The parental controls revealed some variation in expression of core ECM proteins, including Pericardin, and both Collagen-IV subunits ( viking and Cg25c or Col4a1 ).…”

“…Giant larvae were allowed to grow for 14 days at 25 0 C before being sacrificed for analysis, parental controls were taken at wandering third instar. For high fat diet treatment, 30% volume was supplemented with coconut oil and flies were maintained at room temperature (Andrews et al 2023).…”