Department of Medicine.
Department of Neuroscience, and.
J Clin Invest. 2023 Apr 3;133(7):e164185. doi: 10.1172/JCI164185.
Glucose homeostasis can be improved after bariatric surgery, which alters bile flow and stimulates gut hormone secretion, particularly FGF15/19. FGFR1 expression in AGRP-expressing cells is required for bile acids' ability to improve glucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each of their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp-B, is regulated by bile acids. We generated an Agrp-B knockin FLP/knockout allele. AGRP-B-expressing cells are found in endocrine cells of the pars tuberalis and coexpress diacylglycerol lipase B - an endocannabinoid biosynthetic enzyme - distinct from pars tuberalis thyrotropes. AGRP-B expression is also found in the folliculostellate cells of the pituitary's anterior lobe. Mice without AGRP-B were protected from glucose intolerance induced by high-fat feeding but not from excess weight gain. Chemogenetic inhibition of AGRP-B cells improved glucose tolerance by enhancing glucose-stimulated insulin secretion. Inhibition of the AGRP-B cells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after cessation of the DREADD-mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis that is regulated by long-term stability of food availability.
体重减轻手术后葡萄糖内环境稳态可以得到改善，这一过程改变了胆汁流动并刺激了肠道激素的分泌，尤其是 FGF15/19。成纤维细胞生长因子受体 1（FGFR1）在表达 AgRP 的细胞中的表达是胆汁酸改善葡萄糖控制能力所必需的。我们发现，鼠 Agrp 基因有 3 个启动子/增强子区域，分别指导其自身 AGRP 转录本的转录。这些 Agrp 启动子/增强子之一，Agrp-B，受胆汁酸调控。我们生成了 Agrp-B 敲入 FLP/敲除等位基因。Agrp-B 表达细胞存在于垂体结节部的内分泌细胞中，并共同表达二酰基甘油脂肪酶 B——一种内源性大麻素生物合成酶——与结节部促甲状腺素细胞不同。Agrp-B 的表达也存在于垂体前叶的滤泡星状细胞中。缺乏 Agrp-B 的小鼠对高脂肪喂养引起的葡萄糖不耐受具有保护作用，但对体重增加没有保护作用。AGRP-B 细胞的化学遗传抑制通过增强葡萄糖刺激的胰岛素分泌来改善葡萄糖耐量。抑制 AGRP-B 细胞也会导致体重减轻。在 DREADD 介导的抑制停止后长达 6 周，改善的葡萄糖耐量和减轻的体重持续存在，这表明存在葡萄糖内环境稳态的生物学开关，其受食物供应长期稳定性的调节。
