Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis

Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.