PGC-1/Spargel Counteracts High-Fat-Diet-Induced Obesity and Cardiac Lipotoxicity Downstream of TOR and Brummer ATGL Lipase

Abstract

SUMMARY Obesity and metabolic syndrome are associated with an increased risk for lipotoxic cardiomyopathy, which is strongly correlated with excessive accumulation of lipids in the heart. Obesity- and type 2 diabetes-related disorders have been linked to altered expression of the transcriptional cofactor PGC-1α, which regulates the expression of genes involved in energy metabolism. Using Drosophila, we identify PGC-1/spargel (PGC-1/srl) as a key antagonist of high-fat diet (HFD)-induced lipotoxic cardiomyopathy. We find that HFD-induced lipid accumulation and cardiac dysfunction are mimicked by reduced PGC-1/srl function and reversed by PGC-1/srl overexpression. Moreover, HFD feeding lowers PGC-1/srl expression by elevating TOR signaling and inhibiting expression of the Drosophila adipocyte triglyceride lipase (ATGL, Brummer), both of which function as upstream modulators of PGC-1/srl. The lipogenic transcription factor SREBP also contributes to HFD-induced cardiac lipotoxicity, likely in parallel with PGC-1/srl. These results suggest a regulatory network of key metabolic genes that modulates lipotoxic heart dysfunction.

Drosophilaas a model to study obesity and metabolic disease

“…Obese Drosophila exhibited increased cardiac steatosis and fibrosis compared with control flies, supporting an analogous burden to the insect and human hearts (Birse et al, 2010;Diop et al, 2015;Hardy et al, 2015;Na et al, 2013). Heart failure rate is highest in obese flies fed high-calorie diets and lowest in lean low-calorie-fed flies (Bazzell et al, 2013).…”

“…1) can exhibit arrhythmic beating, fibrosis and cardiac failure, which is exacerbated during obesity, similar to the diseased human heart (Diop et al, 2015;Hardy et al, 2015;Heinrichsen et al, 2014). Although their ontogeny differs, the Drosophila heart is an innervated multichambered tube that circulates the hemolymph via an open circulatory system.…”

“…Heart function can be measured by highspeed video analysis of the heart rate in vivo, also known as Semiautomated Optical Heartbeat Analysis (SOHA), enabling quantification of systolic and diastolic strength, heart rate, heart period and arrhythmia (Cammarato et al, 2015). Such studies of heart function have been used to identify protective roles for cardiac proliferator-activated receptor-γ coactivator-1 (PGC-1; also called Spargel in the fly) and Bmm (Diop et al, 2015) and a deleterious role for the cardiac target of rapamycin (TOR) pathway (Birse et al, 2010) in flies with diet-induced obesity and cardiovascular disease.…”

Pathologies et vieillissement cardiaque

“…Cette enzyme qui cible in vivo la tubuline alpha est ainsi une cible thé-rapeutique prometteuse pour traiter des patients atteints de certaines formes de fibrillation atriale. [33]. La versatilité des approches génétiques a donc permis de dresser, chez la drosophile, une carte intégrée des réseaux molécu-laires impliqués dans les dysfonctions cardiaques liées à certaines perturbations métaboliques (Figure 3).…”

“…Cet effet, localisé au niveau du muscle cardiaque, n'a cependant pas de conséquence sur la longévité, sans doute en raison de la détérioration liée à l'âge d'autres organes essentiels. Cette observation souligne l'intérêt particulier de la mouche pour l'analyse du vieillissement cardiaque [33] 'un livre ou inventée, il faudra faire le choix des ingrédients, les mélanger et les cuire de manière appropriée afin de ne pas altérer les substances actives qui composent les ingrédients. Une fois la cuisson terminée, il faudra analyser le goût et si nécessaire prévoir son amélioration.…”