The Effects of INDY on Fly Metabolism

Abstract The Indy (I’m not dead yet) gene encodes a plasma membrane citrate transporter in Drosophila. INDY reduction affects metabolism and extends longevity of flies and worms. In flies, INDY is predominantly expressed in the midgut, fat body and oenocytes, tissues with a key role in metabolism. We hypothesize that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve intestinal stem cell (ISC) homeostasis and slows aging by modifying Insulin/Insulin-like signaling (IIS), which is a key nutrient sensing pathway. Our second goal was to examine the role of JAK/STAT signaling pathway, which activates epithelial renewal in the gut, in response to aging-related stressors. We hypothesize that Indy reduction has effects on the microbiome, preventing bacterial overgrowth and altering community diversity, leading to extended longevity in a JAK/STAT-mediated fashion. Our data suggest that effects of Indy reduction is mediated by reduced IIS and JAK/STAT pathways

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The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Metabolites ◽

10.3390/metabo11100705 ◽

2021 ◽

Vol 11 (10) ◽

pp. 705

Author(s):

Kavitha Kannan ◽

Blanka Rogina

Keyword(s):

Stem Cell ◽

Fat Body ◽

Metabolic Adaptation ◽

Caloric Content ◽

Oxygen Species ◽

Lipid Levels ◽

Cell Homeostasis ◽

Citrate Transporter ◽

Gene Expression Levels

I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.

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THE EFFECTS OF INDY ON FLY HEALTH

Innovation in Aging ◽

10.1093/geroni/igz038.367 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S97-S98

Author(s):

Blanka Rogina ◽

Pooja Patel ◽

Jacob Macro ◽

Michael Li ◽

Ryan Rogers

Keyword(s):

Fat Body ◽

Physiological Function ◽

Krebs Cycle ◽

Nutrient Sensing ◽

Membrane Transporter ◽

Beneficial Effects ◽

Intestinal Integrity ◽

Krebs Cycle Intermediates ◽

Plasma Membrane Transporter

Abstract Indy (I’m not dead yet) gene encodes a plasma membrane transporter of Krebs’ cycle intermediates with highest affinity for citrate. Indy is the fly homolog of a mammalian mIndy (SLC13A5), which has the same physiological function. Reduced expression of the Indy gene extends longevity in fruit flies and worms. Genetic and pharmacological INDY reduction affects metabolism in flies, worms, mice, rats and non-human primates by affecting the levels of cytoplasmic citrate. In flies, INDY is predominantly expressed in the midgut, fat body and oenocytes, all tissues with a key role in metabolism. Our first goal was to examine our working hypothesis that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve intestinal stem cell (ISCs) homeostasis and slows aging by modifying Insulin/Insulin-like signaling (IIS). ISC homeostasis is vital for midgut homeostasis and contributes to health and longevity. We found that reduction of Indy preserves ISC homeostasis and intestinal integrity. The IIS is a key nutrient sensing pathway, which regulates growth, metabolism and longevity. Indy reduction is associated with decreased IIS activity. Our second goal was to examine the role of IIS in Indy mediated changes in ISC homeostasis and health. We found that at least some of INDY’s beneficial effects on fly health are mediated by the IIS.

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Dual role of BMP signaling in the regulation of Drosophila intestinal stem cell self-renewal

Fly ◽

10.1080/19336934.2017.1384104 ◽

2017 ◽

Vol 11 (4) ◽

pp. 297-302 ◽

Cited By ~ 6

Author(s):

Aiguo Tian ◽

Jin Jiang

Keyword(s):

Stem Cell ◽

Dual Role ◽

Bmp Signaling ◽

Intestinal Stem Cell ◽

Self Renewal

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Msi RNA-binding proteins control reserve intestinal stem cell quiescence

The Journal of Cell Biology ◽

10.1083/jcb.201604119 ◽

2016 ◽

Vol 215 (3) ◽

pp. 401-413 ◽

Cited By ~ 32

Author(s):

Maryam Yousefi ◽

Ning Li ◽

Angela Nakauka-Ddamba ◽

Shan Wang ◽

Kimberly Davidow ◽

...

Keyword(s):

Stem Cell ◽

Rna Binding ◽

Rna Binding Proteins ◽

Intestinal Stem Cell ◽

Stem Cell Population ◽

Cell Compartment ◽

Stem Cell Quiescence ◽

Cell Quiescence ◽

Necessary And Sufficient

Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive Wnthigh ISC that fuels turnover during homeostasis and a reserve, radioresistant Wntlow/off ISC capable of generating active Wnthigh ISCs. We examined the role of the Msi family of oncoproteins in the ISC compartment. We demonstrated that Msi proteins are dispensable for normal homeostasis and self-renewal of the active ISC, despite their being highly expressed in these cells. In contrast, Msi proteins are required specifically for activation of reserve ISCs, where Msi activity is both necessary and sufficient to drive exit from quiescence and entry into the cell cycle. Ablation of Msi activity in reserve ISCs rendered the epithelium unable to regenerate in response to injury that ablates the active stem cell compartment. These findings delineate a molecular mechanism governing reserve ISC quiescence and demonstrate a necessity for the activity of this rare stem cell population in intestinal regeneration.

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