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

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      MOHAN-DISSERTATION.pdf (5.558Mb)
      Date
      2015-05-20
      Author
      Mohan, Haneesha 1987-
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      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.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Veterinary Biomedical Sciences
      Program
      Veterinary Biomedical Sciences
      Supervisor
      local.embargo.terms
      Committee
      Unniappan, Suraj; Machin, Karen; Forsyth, George; Hiebert, Linda; Desai, Kaushik; Chelikani, Prasanth
      Copyright Date
      May 2015
      URI
      http://hdl.handle.net/10388/12641
      Subject
      Nucleobindin-2, Nesfatin-1, Development, Nutrients, Metabolism, Energy Balance
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