Nesfatin-1 and Nesfatin-1-Like Peptide (NLP) Regulation of Energy Balance in Mice

Abstract

Whole-body energy homeostasis is regulated by the endocrine system via a spectrum of hormones. Nucleobindin-1 and -2 (NUCB1 and NUCB2) are multi-domain calcium and DNA binding proteins. Nesfatin-1 encoded in NUCB2 is a multifunctional peptide with insulinotropic, glucoregulatory, fat influencing, cardiovascular and reproductive functions. While nesfatin-1 modulates enteric hormones, whether it is indispensable for normal enteric hormone milieu is unclear. Nesfatin-1 stimulates glucose-stimulated insulin secretion. It is abundantly expressed in the intestinal submucosa. However, its direct actions on intestinal glucose uptake are unknown. In pancreas, nesfatin-1 is exclusive to the β cells of islets. Whole-body disruption of NUCB2/nesfatin-1 in mice displays a sexually dimorphic effect, with alterations in body weight, food intake and energy homeostasis. How critical are β cell specific nesfatin-1 in glucose and energy homeostasis? Similarly, NUCB1 encodes a nesfatin-1-like peptide (NLP) that is insulinotropic. Whether NLP is a naturally occurring endogenous peptide remains unknown. The central hypothesis of this thesis research is that nesfatin-1 is crucial for enteric hormone milieu, intestinal glucose absorption, whole-body energy homeostasis, and NLP is an endogenous peptide. This thesis research led to four major findings. First, it was found that mice lacking NUCB2/nesfatin-1 had altered enteric hormone expression. Second, it was determined that lack of nesfatin-1 modulates major intestinal glucose transporters in a region-specific manner, and influences intestinal glucose transport. Third, the lack of nesfatin-1 in β cells alters glucose tolerance and metabolic parameters and the effects display sexual dimorphism. Fourth, naturally occurring NLP was identified as a metabolic peptide. Together, this research provides new information on the essential role of endogenous nesfatin-1 on energy homeostasis and establishes NLP as a naturally occurring bioactive peptide.