以果蠅與小鼠模式探討胃酸對代謝與壽命之調控

Abstract

老化與代謝症候群是當代醫學的重要課題，近年來果蠅廣被應用於這些問題的基礎研究。在先前的研究中，我們透過突變株篩選，發現消化道中酸分泌缺失的果蠅會出現類似代謝症候群的表現型(肥胖及高三酸甘油酯)，且其壽命顯著縮短，顯示消化道酸鹼度可能影響老化與代謝過程。 為延續上述成果，本計畫繼續透過基因操弄與藥物介入等方式，建立消化道中段酸分泌異常的果蠅模式，進而系統性的探討消化道中段酸分泌不足對於老化與代謝的影響。在代謝表現型方面，我們發現腸道中段酸度不足的果蠅有體脂肪含量與體重上升，與飢餓耐受度增加等現象。在老化過程方面，我們發現這些果蠅的消化道障壁功能異常提早出現，壽命也顯著縮短。我們也在胃酸抑制的小鼠模式上觀察到類似的代謝表現型(肥胖及高脂血症)，進一步印證了消化道中段酸度在代謝調控方面的角色。此外，我們的初步研究顯示果蠅腸道中段酸度會隨年齡下降，而卡路里節制可以減緩此情形，這暗示卡路里節制之所以能延長壽命，部分可能是透過維持腸道酸度而達成。期盼未來能夠藉由本研究所建立的動物模式，進一步釐清消化道酸鹼度與代謝及老化的關聯性。

Previous work in our lab showed that Drosophila melanogaster harboring hypomorphic mutations in vha16-1 gene, which encodes vacuolar H+-ATPase subunit c and is highly expressed in middle midgut, exhibit reduced midgut acidification, as well as metabolic syndrome-like phenotypes (obesity, elevated triacylglycerol content), better starvation resistance, and a reduced lifespan. This observation led to the hypothesis that midgut acidity may be a regulator of systemic metabolism. In this project, we established different fly models to test the hypothesis. We demonstrated that both genetic and pharmacological models of flies with deficient midgut acidification display increased triacylglycerol content and body weight, as well as a reduced lifespan. We also found that flies with deficient midgut acidification exhibit accelerated gut barrier dysfunction. Furthermore, our preliminary data showed that midgut acidity decreases with age in wild-type flies, and calorie restriction attenuates the age-dependent decline in midgut acidity. To explore whether the metabolic role of midgut acidity is conserved across species, we examined mice treated with proton pump inhibitor. These mice exhibited metabolic phenotypes reminiscent of flies with deficient midgut acidification, including reduced gastric juice acidity, increased serum triacylglycerol and cholesterol, and increased body weight gain. Taken together, our studies identified midgut acidity as a novel player in gut homeostasis and systemic metabolism.