Abstract
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.
Highlights
The heart, being the sole pumping engine in the body, utilizes large amounts of fatty acids as energy-providing substrates [1]
Using Hand-Gal4 to drive the simultaneous knockdown of esg and sna, or the simultaneous knockdown of esg and wor in the heart, which led to an approximate 80%, 40%, or over 90% reduction in the cardiac levels of sna, esg, or wor, respectively (S2A– S2C Fig), we found an accumulation of neutral fat in the esg, sna- and esg, wor-double knockdown hearts, as shown by staining with Bodipy (Fig 1A and 1A”), a strong fluorescent lipophilic dye
We found that the fat body transcript levels of the free fatty acid (FFA) biosynthesis genes acyl-coA carboxylase (ACC) but not ATP-citrate lyase (ATPCL) was significantly reduced in the cardiac Sna-overexpressing flies and elevated in the cardiac Sna TF-knockdown flies relative to control flies (Fig 6F and 6G)
Summary
The heart, being the sole pumping engine in the body, utilizes large amounts of fatty acids as energy-providing substrates [1]. Our recent work revealed that the heart is an important source of apolipoprotein B (apoB)-containing lipoproteins (apoB- lipoproteins) and that cardiac-derived apoB-lipoproteins serve as an important determinant of whole-body lipid metabolism by controlling the uptake and transport of dietary lipids from the intestine to other tissues [9]. Together, these findings provide compelling evidence supporting a critical role of the heart in systemic lipid metabolic control; the underlying molecular mechanisms remain incompletely understood
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