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.
Highlights
The incidence of complex metabolic disorders has been on the rise for the past three decades, comprising an epidemic of ever-increasing severity
We have found that loss of the Drosophila homolog of the founding member of the sirtuin family, sir2, leads to age-progressive metabolic disease with symptoms similar to those of type 2 diabetes
We show that the Drosophila Hepatocyte Nuclear Factor 4 (HNF4) nuclear receptor is deacetylated and stabilized by Sir2, PLOS Genetics | DOI:10.1371/journal.pgen
Summary
The incidence of complex metabolic disorders has been on the rise for the past three decades, comprising an epidemic of ever-increasing severity. Much of this can be attributed to an increase in the prevalence of type 2 diabetes accompanied by insulin resistance, the development of which is complex and poorly understood These trends have prompted widespread changes in public policy and a shift in biomedical research toward improving our understanding of the genetic and environmental factors that contribute to insulin resistance and its progression to a more severe disease state. One focus for these studies has been the sirtuin family of NAD+-dependent deacetylases, which play a central role in coupling metabolic state to systemic physiology. The multiple downstream targets of SIRT1, combined with its dependence on NAD+, establish it as a pivotal energy sensor that couples cellular redox state to metabolic control
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
