Activation of ChAT+ neuron in dorsal motor vagus (DMV) increases blood glucose through the regulation of hepatic gene expression in mice.

The brain and peripheral organs communicate through hormones and neural connections. Proper communication is required to maintain normal whole-body energy homeostasis. In addition to endocrine system, from the perspective of neural connections for metabolic homeostasis, the role of the sympathetic nervous system has been extensively studied, but understanding of the parasympathetic nervous system is limited. The liver plays a central role in glucose and lipid metabolism. This study aimed to clarify the innervation of parasympathetic nervous system in the liver and its functional roles in metabolic homeostasis. The liver-specific parasympathetic nervous system innervation (PNS) was shown by tissue clearing, immunofluorescence and transgenic mice at the three-dimensional histological level. The parasympathetic efferent signals were manipulated using a chemogenetic technique and the activation of ChAT+ parasympathetic neurons in dorsal motor vagus (DMV) results in the increased blood glucose through the elevated hepatic gluconeogenic and lipogenic gene expression in the liver. Thus, our study showed the evidence of ChAT+ parasympathetic neurons in the liver and its role for hepatic parasympathetic nervous signaling in glucose homeostasis through the regulation of hepatic gene expression.

PRMT1 Is Required for the Maintenance of Mature ß-Cell Identity.

Loss of functional ß-cell mass is an essential feature of type 2 diabetes, and maintaining mature ß-cell identity is important for preserving a functional ß-cell mass. However, it is unclear how ß-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature ß-cell identity. Prmt1 knockout in fetal and adult ß-cells induced diabetes, which was aggravated by high-fat diet-induced metabolic stress. Deletion of Prmt1 in adult ß-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of ß-cell identity. The expression levels of genes involved in mature ß-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult ß-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and ß-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining ß-cell identity by regulating chromatin accessibility.

Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3.

BACKGROUND: Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated. METHODS: Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells. RESULTS: Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and ß-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3. CONCLUSION: PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

Loss of ß-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits.

Loss of pancreatic islet ß-cell mass and ß-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing ß-cells can convert into glucagon-containing α-cells ex vivo. This loss of ß-cell identity was characterized by the presence of ß-cell transcription factors (Nkx6.1, Pdx1) in glucagon(+) cells. Here, we investigated whether the loss of ß-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin(+) cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1(+)glucagon(+)insulin(-) cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1(+)glucagon(+)insulin(-) cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of ß-cell identity occurs in T2DM and could contribute to the decrease of functional ß-cell mass. Maintenance of ß-cell identity is a potential novel strategy to preserve ß-cell function in diabetes.