Hedgehog signaling promotes lipolysis in adipose tissue through directly regulating Bmm/ATGL lipase

Hedgehog (Hh) signaling has been shown to regulate multiple developmental processes, however, it is unclear how it regulates lipid metabolism. Here, we demonstrate that Hh signaling exhibits potent activity in Drosophila fat body, which is induced by both locally expressed and midgut-derived Hh proteins. Inactivation of Hh signaling increases, whereas activation of Hh signaling decreases lipid accumulation. The major lipase Brummer (Bmm) acts downstream of Smoothened (Smo) in Hh signaling to promote lipolysis, therefore, the breakdown of triacylglycerol (TAG). We identify a critical Ci binding site in bmm promoter that is responsible to mediate Bmm expression induced by Hh signaling. Genomic mutation of the Ci binding site significantly reduces the expression of Bmm and dramatically decreases the responsiveness to Ci overexpression. Together, our findings provide a model for lipolysis to be regulated by Hh signaling, raising the possibility for Hh signaling to be involved in lipid metabolic and/or lipid storage diseases.