Abstract
Nesfatin-1 is secreted, meal-responsive anorexigenic peptide encoded in the precursor nucleobindin-2 [NUCB2]. Circulating nesfatin-1 increases post-prandially, but the dietary components that modulate NUCB2/nesfatin-1 remain unknown. We hypothesized that carbohydrate, fat and protein differentially regulate tissue specific expression of nesfatin-1. NUCB2, prohormone convertases and nesfatin-1 were detected in mouse stomach ghrelinoma [MGN3-1] cells. NUCB2 mRNA and protein were also detected in mouse liver, and small and large intestines. MGN3-1 cells were treated with glucose, fatty acids or amino acids. Male C57BL/6 mice were chronically fed high fat, high carbohydrate and high protein diets for 17 weeks. Quantitative PCR and nesfatin-1 assays were used to determine nesfatin-1 at mRNA and protein levels. Glucose stimulated NUCB2 mRNA expression in MGN3-1 cells. L-Tryptophan also increased NUCB2 mRNA expression and ghrelin mRNA expression, and nesfatin-1 secretion. Oleic acid inhibited NUCB2 mRNA expression, while ghrelin mRNA expression and secretion was enhanced. NUCB2 mRNA expression was significantly lower in the liver of mice fed a high protein diet compared to mice fed other diets. Chronic intake of high fat diet caused a significant reduction in NUCB2 mRNA in the stomach, while high protein and high fat diet caused similar suppression of NUCB2 mRNA in the large intestine. No differences in serum nesfatin-1 levels were found in mice at 7 a.m, at the commencement of the light phase. High carbohydrate diet fed mice showed significantly elevated nesfatin-1 levels at 1 p.m. Serum nesfatin-1 was significantly lower in mice fed high fat, protein or carbohydrate compared to the controls at 7 p.m, just prior to the dark phase. Mice that received a bolus of high fat had significantly elevated nesfatin-1/NUCB2 at all time points tested post-gavage, compared to control mice and mice fed other diets. Our results for the first time indicate that nesfatin-1 is modulated by nutrients.
Highlights
Nesfatin-1 [NEFA/NUCB2-encoded satiety and fat-influencing protein-1] is a potent anorexigenic peptide implicated in the regulation of energy balance and glucose homeostasis [1, 30]
NUCB2, PC 1/3 and PC 2 mRNAs are expressed in MGN3-1 cells and NUCB2 mRNA is expressed in the stomach, liver, small intestine and large intestine of male mice
Our findings suggest that the effects of diets on the expression of endogenous NUCB2/ nesfatin-1 are myriad, with specific effects on mRNA expression versus secretion, in a dose and time dependent manner
Summary
Nesfatin-1 [NEFA/NUCB2-encoded satiety and fat-influencing protein-1] is a potent anorexigenic peptide implicated in the regulation of energy balance and glucose homeostasis [1, 30]. It is an 82 amino acid peptide derived from the precursor protein, nucleobindin-2 (NUCB2) [1]. Insulin producing beta cells co-express nesfatin-1 in the pancreatic islets of rats and mice [2, 4, 11], suggesting that nesfatin-1 could play an important role in insulin secretion and glucose homeostasis [4, 29]. NUCB2 mRNA expression in purified gastric mucosal endocrine cells was found to be higher than in the brain of rats [13]. The wide distribution of NUCB2/nesfatin-1 in central and peripheral tissues points to a role for nesfatin-1 in regulating metabolism
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