Nucleobindin-1 <i>(Nucb1)</i> disruption affects feeding, metabolism, and glucose homeostasis in mice in an age-, sex-, diet- and light cycle-dependent manner

Abstract Background Nesfatin-1 (NESF-1), encoded in the calcium and DNA binding protein (Nucleobindin 2, NUCB2) is an orphan ligand with metabolic effects. Recently, our lab provided evidence for a NESF-1-like peptide (NLP) in a NUCB2-related precursor, NUCB1, in zebrafish and rodents. This research aims to determine whether endogenous NUCB1 is critical for energy homeostasis. Methods and Main Findings Global genetic disruption of Nucb1 ( Nucb1 knockout/KO mice) led to increased food intake in chow-fed male and female mice across different points of light and dark phases. A similar increase in water intake was seen in female Nucb1 KO mice but not in males. White adipose tissue weight was significantly increased in male and female Nucb1 KO mice. Dark phase total activity was increased in male Nucb1 KO mice, while it was decreased in female Nucb1 KO mice compared to wildtype littermates. Energy derived from carbohydrates was raised during the dark phase; while energy derived from fat was significantly decreased in both male and female Nucb1 KO mice. Male Nucb1 KO mice were lighter in the early stages, but these differences disappeared as they aged. Meanwhile, no differences in bodyweight were observed in female Nucb1 KO mice. Male Nucb1 KO mice handled glucose better during an oral glucose tolerance test, while the opposite effect was found in an intraperitoneal (IP) glucose tolerance test. The above results from chow-fed mice were largely true in 10% and 60% fat diet-fed mice. A significant two-way interaction between mice group and time was observed on weekly food intake of male and female Nucb1 KO mice fed control fat diet, but not in 60% fat-fed group. Handling of blood glucose during IPGTT was better in male Nucb1 KO mice fed both diets, while such an effect was not observed in female KO mice. A significant two-way interaction of mice group and time on food and water intake value in 24 h was observed for male Nucb1 KO mice fed 10% fat diet. The total physical activity during the dark phase and energy expenditure during the light phase showed a sex-specific pattern in male and female Nucb1 KO mice fed 10% fat diet. Energy expenditure showed a sex-specific pattern in Nucb1 KO mice during the dark phase. Moreover, adiposity increased in male Nucb1 KO mice fed a high fat diet. Conclusions Our results indicate that the disruption of Nucb1 leads to metabolic changes in vivo . The phenotype appears to depend on sex, age, diet, and the light-dark cycle. In conclusion, these outcomes furnish important evidence supporting critical roles for endogenous NUCB1 in energy homeostasis.

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