Harada Kazuki, Wada Eiji, Osuga Yuri, Shimizu Kie, Uenoyama Reiko, Hirai Masami Yokota, Maekawa Fumihiko, Miyazaki Masao, Hayashi Yukiko K, Nakamura Kazuaki, Tsuboi Takashi
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902, Japan; Health and Environmental Risk Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
Department of Pathophysiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku, Tokyo 160-8402, Japan.
Mol Metab. 2025 Jan;91:102072. doi: 10.1016/j.molmet.2024.102072. Epub 2024 Dec 11.
Arginine vasopressin (AVP), known as an antidiuretic hormone, is also crucial in metabolic homeostasis. Although AVP receptor-deficient mice exhibit various abnormalities in glucose and lipid metabolism, the mechanism underlying these symptoms remains unclear. This study aimed to explore the involvement of the gut hormones including glucagon-like peptide-1 (GLP-1) and microbiota as essential mediators.
We used the mouse GLP-1-secreting cell line, GLUTag, and performed live cell imaging to examine the contribution of V1a and V1b vasopressin receptors (V1aR and V1bR, respectively) to GLP-1 secretion. We next investigated the hormone dynamics of V1aR-deficient mice (V1aR mice), V1bR-deficient mice (V1bR mice), and V1aR/V1bR-double deficient mice (V1aRV1bRmice).
AVP induced the increase in intracellular Ca levels and GLP-1 secretion from GLUTag cells in a V1aR and V1bR-dependent manner. AVP receptor-deficient mice, particularly V1aRV1bR mice, demonstrated impaired secretion of GLP-1 and peptide YY secreted by enteroendocrine L cells. V1aRV1bRmice also exhibited abnormal lipid accumulation in the brown adipose tissue and skeletal muscle. We discovered that V1aRV1bR mice showed increased Paneth cell-related gene expression in the small intestine, which was attributed to increased fecal butyric acid levels. Exposure to butyric acid reduced GLP-1 secretion in L cell line. Additionally, human Paneth cell-related gene expressions negatively correlated with that of V1 receptor genes.
The deficiency in V1 receptor genes may increase gut butyric acid levels and impair the function of L cells, thus dysregulating lipid homeostasis in the brown adipose tissue and skeletal muscle. This study highlights the importance of appropriate control of the gut microbiota and its metabolites, including butyric acid, for the optimum functioning of enteroendocrine cells.
精氨酸加压素（AVP），作为一种抗利尿激素，在代谢稳态中也至关重要。尽管AVP受体缺陷小鼠在葡萄糖和脂质代谢方面表现出各种异常，但其潜在机制仍不清楚。本研究旨在探讨包括胰高血糖素样肽-1（GLP-1）和微生物群在内的肠道激素作为重要介质的作用。
我们使用小鼠GLP-1分泌细胞系GLUTag，并进行活细胞成像，以研究V1a和V1b血管加压素受体（分别为V1aR和V1bR）对GLP-1分泌的作用。接下来，我们研究了V1aR缺陷小鼠（V1aR小鼠）、V1bR缺陷小鼠（V1bR小鼠）和V1aR/V1bR双缺陷小鼠（V1aRV1bR小鼠）的激素动态变化。
AVP以V1aR和V1bR依赖的方式诱导GLUTag细胞内钙水平升高和GLP-1分泌增加。AVP受体缺陷小鼠，尤其是V1aRV1bR小鼠，表现出肠内分泌L细胞分泌的GLP-1和肽YY受损。V1aRV1bR小鼠在棕色脂肪组织和骨骼肌中也表现出异常的脂质积累。我们发现V1aRV1bR小鼠小肠中潘氏细胞相关基因表达增加，这归因于粪便中丁酸水平升高。暴露于丁酸会降低L细胞系中的GLP-1分泌。此外，人类潘氏细胞相关基因表达与V1受体基因表达呈负相关。
V1受体基因缺陷可能会增加肠道丁酸水平并损害L细胞功能，从而导致棕色脂肪组织和骨骼肌脂质稳态失调。本研究强调了适当控制肠道微生物群及其代谢产物（包括丁酸）对于肠内分泌细胞最佳功能的重要性。
