Ano4 and Metabolic Health

PROJECT SUMMARY Obesity is a major risk factor for many chronic medical conditions, including diabetes, cardiovascular disease, depression, and cancer. Elucidating the neural mechanisms that regulate feeding behavior and body weight control is critically needed towards the development of effective strategies to combat obesity and its co- morbidities. We discovered that anoctamin 4 (Ano4, an ion channel) is abundantly expressed in the area postrema (AP) in the hindbrain. Activation of these APAno4 neurons increase food intake and blood glucose in mice. Importantly, a large-scale human genetic study established the association of the ANO4 gene mutation with human obesity, but the causality of this association has not been tested. The first objective is to determine physiological relevance of APAno4 neurons in energy/glucose balance. We will use both gain- and loss-of-function models to establish the function of the APAno4 neurons on feeding and valence behavior, as well as long-term regulation of body weight and glucose homeostasis. The second objective is to use a Cas9-mediated DNA editing to delete Ano4 only in AP neurons, and to determine physiological functions of the Ano4 channel on the excitability of AP neurons and on the whole-body energy/glucose balance. The third objective is to use a humanized Ano4 knock-in mouse model (mimicking the obesity-associated human ANO4 mutation) to determine whether this mutation causes obesity in mice and alters Ano4 channel functions. Completion of the proposed research will identify a novel target that regulates body weight balance in mice and humans, and provide the necessary framework to develop therapeutic strategies towards treating obesity.