Midgut Acidity Regulates Metabolism and Lifespan in Drosophila melanogaster and Mice
Date Issued
2016
Date
2016
Author(s)
Lin, Wei-Sheng
Abstract
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.
Subjects
midgut acidity
metabolism
obesity
metabolic syndrome
aging
lifespan
SDGs
Type
thesis