Data from: The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.尽管二十年前，肝细胞核因子4α（HNF4A）的突变已被确定为青少年发病的成年型糖尿病1型（Maturity Onset Diabetes of the Young 1, MODY1）的致病原因，但该核受体（nuclear receptor）调控葡萄糖稳态（glucose homeostasis）的具体分子机制仍不明确。本研究发现，果蝇（Drosophila）HNF4缺失可重现MODY1的典型症状，包括成年发病的高血糖、糖耐量异常以及葡萄糖刺激的胰岛素分泌（glucose-stimulated insulin secretion, GSIS）功能受损。上述缺陷与dHNF4在维持线粒体功能及表达Hex-C（MODY2基因葡萄糖激酶（Glucokinase）的同源基因）中的作用密切相关。在脂肪体（fat body）与胰岛素生成细胞（insulin-producing cells）中，dHNF4是维持葡萄糖稳态所必需的，其可通过促进向氧化磷酸化（oxidative phosphorylation）与成年过渡期葡萄糖刺激胰岛素分泌的发育转换，发挥相应功能。本研究不仅建立了MODY1的动物模型，还明确了代谢发育重编程以支撑成熟个体能量需求的关键机制。