Characterization of Endogenous Nucleobindin-2/Nesfatin-1 in Rodents

Abstract

Whole body energy homeostasis is regulated by the endocrine system. Nesfatin-1 is a newly identified multifunctional metabolic peptide with insulinotropic, endocrine, glucoregulatory, fat reducing and cardiovascular functions. While nesfatin-1 tissue expression and secretion are considered meal responsive, it is unknown whether macronutrients and/or development regulate its secretion. Is endogenous nesfatin-1 critical for energy balance? The central hypothesis of this thesis research is that the tissue specific expression of NUCB2/nesfatin-1 is regulated developmentally, and by nutrients, and that endogenous NUCB2/nesfatin-1 is critical for the maintenance of energy homeostasis. The specific objectives of this research were to determine the developmental, and nutrient regulated expression of NUCB2/nesfatin-1, and to characterize the metabolic phenotype of mice lacking NUCB2/nesfatin-1. Three key findings were made in this research. First, it was found that NUCB2/nesfatin-1 presents an ontogenic pattern of expression in the gastroenteropancreatic tissues and serum of rats. An age-dependent co-expression of related peptides, ghrelin and its processing enzyme, ghrelin-O-acyl transferase (GOAT), and nesfatin-1 processing prohormone convertases were also found in the endocrine pancreas. Second, it was determined that the NUCB2 mRNA expression and NUCB2/nesfatin-1 secretion in mice are influenced by nutrients in a tissue specific manner in vitro and in vivo, and it depends on the duration of exposure to specific diets tested. This research identified nutrients as major regulators of endogenous NUCB2/nesfatin-1. Third, a sexually dimorphic effect of NUCB2/nesfatin-1 disruption in mice was found, with alterations in body weight, food intake, insulin secretion, glucose homeostasis and energy homeostasis. These data support a metabolic role for endogenous nesfatin-1. Together, this research provides important new information on developmental and cell specific regulation of nesfatin-1 expression, nutrient modulation of its expression and secretion, and an essential role for endogenous nesfatin-1 in maintaining energy homeostasis. For example, endocrine pancreas is an abundant source of nesfatin-1. Absence of endogenous nesfatin-1 causes defects in insulin secretion from islet beta cells, and alters glucose homeostasis. Exogenous nesfatin-1 causes a reduction in body weight. NUCB2 gene disruption resulted in abnormal body weight in mice, further confirming that nesfatin-1 indeed influences body mass.