How Hedgehog Contributes to Centrally Mediated Energy Homeostasis?

PROJECT SUMMARY Obesity contributes to heart disease and diabetes, leading to early mortality. Two-thirds of adults in the United States are overweight, adding to healthcare costs. Yet, energy homeostasis is not fully understood. Recent research has revealed that primary cilia on neurons in the brain play a crucial role in preventing overeating and obesity. Primary cilia are solitary, microtubule-based appendages found on most cell types. These cilia are critical for specific cell-to-cell communication processes, with Hedgehog (HH) signaling being one of the best-understood cilia-mediated pathways. HH is essential for tissue patterning during embryonic development. Interestingly, we discovered that the components of the HH pathway are also present in the adult hypothalamus, and their activity is influenced by feeding status and body composition. Activation of HH signaling in specific neurons leads to hyperphagia and obesity. Thus, HH signals are redeployed after embryonic development and influence adult feeding behavior. First, we seek to build on these insights by determining how HH signaling in the adult hypothalamus controls long-term energy homeostasis. We will identify the sources of HH ligands and the responsive cells within the adult hypothalamus and test whether HH acts acutely to affect neuronal electrophysiological activity critical to controlling feeding behavior. Second, as HH signals can control the ciliary function of a G protein-coupled receptor (GPCR) during development, we hypothesize that HH signals also regulate the function of ciliary GPCRs in neurons involved in adult energy homeostasis. Therefore, we will test whether HH signals control neuronal signaling by MC4R and MCHR1, two ciliary GPCRs involved in energy homeostasis. Both HH signaling and ciliary GPCRs regulate protein kinase A (PKA). Thus, we will also test whether neurons integrate HH signaling and ciliary GPCR output at the level of PKA. We test these hypotheses using complementary in vitro and in vivo studies and both genetic and pharmacological approaches. Together, the experiments involved in this project will reveal how ciliary HH signaling controls adult neuronal activity to regulate long-term energy homeostasis.