In recent years, research on the functions of a previously overlooked organelle, the primary cilium, has experienced a boom. Once thought to be vestigial, the cilium is now known to play crucial roles in a number of developmental processes and diseases. For example, primary cilia are essential in early embryonic development and are required for specification of the left-right body axis as well as for neural tube and limb patterning. Furthermore, human genetic disorders, termed ciliopathies, present with a broad range of clinical features such as cystic kidney disease, retinopathy, anosmia, and obesity. While the analysis of cilia function in embryonic tissues and through development has revealed much about their roles as signaling centers, the functions of cilia in tissue homeostasis in adult mammalian systems remain largely unexplored. This gap in our understanding of cilia function in adults is due to the early embryonic lethality observed in cilia null mutants. In order to overcome this limitation, I am utilizing conditional alleles of genes required for cilia formation, which allows for induced cilia loss in the adult animal after the cilia have fulfilled their roles in embryonic development. Using this approach, the Yoder lab has previously demonstrated an important role for the primary cilium in regulating feeding behavior. Recently published data show that loss of cilia in the adult mouse, and more specifically in the hypothalamus, results in obesity due to hyperphagia. Thus, my central hypothesis is that the primary cilium on neurons in the central nervous system (CNS) act as a sensory organelle involved in reception, transmission, or regulation of satiety signaling. The major objective of this application is to elucidate the connection between the primary cilium and the pathway(s) regulating feeding behavior and satiety signals. To accomplish this objective, I propose: (1) to determine the specific signal(s) lost, gained, or altered in the cilia mouse model that result in hyperphagia and obesity, (2) and to analyze in vitro how neuronal cilia are utilized for the reception and/or transmission of these specific anorexigenic or orexigenic signals. These research goals will not only provide novel insights into how cilia in the CNS function to maintain proper energy balance and homeostasis but will also provide insights as to how cilia on other neurons are utilized. Furthermore, understanding the molecular mechanisms behind the obesity in this mouse model will provide new opportunities for potential therapeutic targets directed at attenuating one of the most pervasive and costly health issues in the United States.
Obesity is one of the most common nutritional disorders in developed societies and is associated with a number of significant health issues including higher risks of type II diabetes mellitus, hypertension, stroke, and heart disease. Recently it has been found that small hair-like organelles found on most cell types of the body called cilia are involved in regulating feeding behavior and defects in cilia lead to obesity through unknown mechanisms. The goal of this project is to uncover how cilia defects alter feeding behavior because a better understanding of the mechanisms behind satiety and appetite will allow for the development of potential therapeutics to treat obesity.
