Grant: CIHR Fellowship

Nucleobindins (NUCB) are calcium and DNA binding proteins. In 2006, nesfatin-1, a novel satiety and fat influencing protein was identified as a processed peptide arising from NUCB2. Our research found a nesfatin-1-like peptide (NLP) in NUCB1. It was found that NLP too acts as a satiety and fat-influencing peptide. Emerging results from our laboratory and other researchers show that both nesfatin-1 and NLP lower fat accumulation in liver cells. The overarching goal of this project is to determine the mechanism of action of nesfatin-1 and NLP in regulating fat levels in the liver. We hypothesize that nesfatin-1 and NLP attenuates fat by increasing its conversion to energy and decreasing its synthesis within liver cells. Both liver cells from humans and mice, and wildtype mice and mice lacking the gene that produces nesfatin-1 and NLP will be used. Under the first aim, the role of nesfatin-1 and NLP on fat uptake, synthesis, and conversion in human and murine liver cells, and the enzymes that facilitate these processes will be studied. In the second aim, the same processes will be studied in mice that lack these peptides due to the disruption of NUCB genes. This approach will enable us to understand the importance of naturally occurring NUCBs on lipid homeostasis in the liver. It is anticipated that nesfatin-1 and NLP attenuates fat accumulation in the liver by affecting enzymes that regulate lipid synthesis. This research has potential implications in diseases including non-alcoholic fatty liver (NAFLD) and lipotoxicity seen in metabolic diseases. The primary applicant will be responsible for the completion of all studies. The two objectives can progress simultaneously and be completed in the funding period.