Cardiac Snail family of transcription factors directs systemic lipid metabolism in Drosophila

Maintenance of normal lipid homeostasis is crucial to heart function. On the other hand, the heart is now recognized to serve an important role in regulating systemic lipid metabolism; however, the molecular basis remains unclear. In this study, we identify the Drosophila Snail family of transcription factors (herein termed Sna TFs) as new mediators of the heart control of systemic lipid metabolism. Overexpression of Sna TF genes specifically in the heart promotes whole-body leanness whereas their knockdown in the heart promotes obesity. In addition, flies that are heterozygous for a snail deficiency chromosome also exhibit systemic obesity, and that cardiac-specific overexpression of Sna substantially reverses systemic obesity in these flies. We further show that genetically manipulating Sna TF levels in the fat body and intestine do not affect systemic lipid levels. Mechanistically, we find that flies bearing the overexpression or inhibition of Sna TFs in the postnatal heart only exhibit systemic lipid metabolic defects but not heart abnormalities. Cardiac-specific alterations of Sna TF levels also do not perturb cardiac morphology, viability, lipid metabolism or fly food intake. On the other hand, cardiac-specific manipulations of Sna TF levels alter lipogenesis and lipolysis gene expression, mitochondrial biogenesis and respiration, and lipid storage droplet 1 and 2 (Lsd-1 and Lsd-2) levels in the fat body. Together, our results reveal a novel and specific role of Sna TFs in the heart on systemic lipid homeostasis maintenance that is independent of cardiac development and function and involves the governance of triglyceride synthesis and breakdown, energy utilization, and lipid droplet dynamics in the fat body. Author summary In this study, we identify a novel and specific role of the Drosophila Snail family of transcription factors (herein termed Sna TFs) in the heart in maintaining normal systemic lipid homeostasis. While the mammalian Snail1 transcription factor has recently been reported to regulate lipid metabolism in the mouse adipose tissue and liver, a systemic metabolic role of the Snail family factors is not known. We provide first demonstration that Sna TFs in the heart regulate lipogenesis and lipolysis, mitochondrial biogenesis and activity, and lipid droplet dynamics in the fat body. We also find that Sna TFs in the heart regulate systemic lipid levels independently of cardiac development and function, cardiac morphology and viability, and cardiac lipid metabolism. We further show that Sna TFs direct the systemic control of lipid levels from the heart and not from other metabolic tissues including the fat body and intestine. Our work therefore provides unique and striking insights into the emerging lipid metabolic functions of Sna family proteins. By defining Sna TFs as new players that mediate the heart regulation of systemic lipid homeostasis, our study also brings forward research in the field of cardiac and metabolism intersection.