ArticlePLoS genetics2016
Sir2 Acts through Hepatocyte Nuclear Factor 4 to maintain insulin Signaling and Metabolic Homeostasis in Drosophila.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 51 citations in OpenAlex.
- Phage display-mediated immuno-PCR to detect low-abundance secreted proteins inProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Transcriptional Control of Lipid Metabolism.Advances in experimental medicine and biology · 2026Review
- Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease.Science advances · 2025Article
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- Targeting SIRT2 in Aging-Associated Fibrosis Pathophysiology.Aging and disease · 2024Review
- Larval density can be used to predict genetic modifiers of glucagon signaling in Drosophila melanogaster.PloS one · 2024Article
- Integrating lipid metabolism, pheromone production and perception by Fruitless and Hepatocyte Nuclear Factor 4.Science advances · 2023Article
- Integrating lipid metabolism, pheromone production and perception by Fruitless and Hepatocyte nuclear factor 4.bioRxiv : the preprint server for biology · 2023Article
- The genomic basis of copper tolerance in Drosophila is shaped by a complex interplay of regulatory and environmental factors.BMC biology · 2022Article
- A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1.G3 (Bethesda, Md.) · 2022Article
- Genetic variation of macronutrient tolerance in Drosophila melanogaster.Nature communications · 2022Article
- Pool-GWAS on reproductive dormancy in Drosophila simulans suggests a polygenic architecture.G3 (Bethesda, Md.) · 2022Article
- The Genetics of Diabetes: What We Can Learn fromInternational journal of molecular sciences · 2021Review
- Developmental ethanol exposure causes central nervous system dysfunction and may slow the aging process in a Drosophila model of fetal alcohol spectrum disorder.Alcohol (Fayetteville, N.Y.) · 2021Article
- Balancing energy expenditure and storage with growth and biosynthesis during Drosophila development.Developmental biology · 2021Review
- What fuels the fly: Energy metabolism inScience advances · 2021Review
- A glucose-supplemented diet enhances gut barrier integrity inBiology open · 2021Article
- Origin and Development of the Adipose Tissue, a Key Organ in Physiology and Disease.Frontiers in cell and developmental biology · 2021Review
- Aging Suppresses Sphingosine-1-Phosphate Chaperone ApoM in Circulation Resulting in Maladaptive Organ Repair.Developmental cell · 2020Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases, which couple cellular metabolism to systemic physiology. Although studies in mouse models have defined a central role for SIRT1 in maintaining metabolic health, the molecular mechanisms remain unclear. Here we show that loss of the Drosophila SIRT1 homolog sir2 leads to the age-progressive onset of hyperglycemia, obesity, glucose intolerance, and insulin resistance. Tissue-specific functional studies show that Sir2 is both necessary and sufficient in the fat body (analogous to the mammalian liver) to maintain glucose homeostasis and peripheral insulin sensitivity. Transcriptional profiling of sir2 mutants by RNA-seq revealed a major overlap with genes regulated by the nuclear receptor Hepatocyte Nuclear Factor 4 (HNF4). Consistent with this, Drosophila HNF4 mutants display diabetic phenotypes similar to those of sir2 mutants, and protein levels for dHNF4 are reduced in sir2 mutant animals. We show that Sir2 exerts these effects by deacetylating and stabilizing dHNF4 through protein interactions. Increasing dHNF4 expression in sir2 mutants is sufficient to rescue their insulin signaling defects, defining this nuclear receptor as an important downstream effector of Sir2 signaling. This study demonstrates that the key metabolic activities of SIRT1 have been conserved through evolution, provides a genetic model for functional studies of phenotypes related to type 2 diabetes, and establishes HNF4 as a critical downstream target by which Sir2 maintains metabolic health.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.