University of Kentucky Center for Cancer and Metabolism (Pilot Project - Jianhang Jia): Hh Signaling in Adipose Tissue and its Regulation of Bmm/ATGL Lipase

Hedgehog (Hh) signaling plays critical roles in pattern formation and cell growth control. Aberrant Hh signaling causes diverse types of cancers. Recent studies have indicated that Hh signaling is also involved in metabolic control; however, the molecular mechanisms are unknown. In the past years, we have contribute significantly to our understanding of Hh signaling mechanisms, producing several major breakthroughs in the field: e.g., Hh signaling activity thresholds are mediated by differential phosphorylation of Smoothened (Smo), a GPCR family member critical for Hh signal transduction; optimal phosphorylation and activation of Smo are regulated by a feedback mechanism involving Fused-Costal2 (Fu-Cos2); PP4 and PP2A are the phosphatases for Smo and transcription factor Ci; ubiquitination promotes Smo endocytosis whereas deubiquitination promotes Smo accumulation on the cell surface; sumoylation counteracts ubiquitination to activate Smo; Hh promotes the production and the release of Ptc-associated PI(4)P to activate Smo through direct interaction with an Arg motif, resulting in an increase of cell surface (in Drosophila) and cilium (in vertebrate) accumulation of Smo. In recent years, we established the fat body, oenocyte, and midgut models to examine lipid metabolic regulation in Drosophila. To elucidate the role of Hh signaling in lipid metabolism, our recent work indicates that Hh signaling upregulates the transcription of Bmm/ATGL lipase in adipose tissue. The overarching goal of this project is to determine how Hh signaling is activated in adipose tissue and how Hh signaling promotes lipolysis. The proposed one-year program of studies uses a combination of genetic and biochemical approaches to build on prior contributions and to transition to newly emergent avenues of inquiry. Two Specific Aims are included: 1) to determine the activation status of Hh signaling in adipose tissue; 2) to determine how Hh signaling promotes the expression of Bmm/ATGL lipase. The knowledge gained from this study will provide novel insights into mechanisms of lipolysis regulation by Hh signaling, which should be a fruitful path to investigate the molecular connection between diet, obesity, diabetes, and cancer.