ABSTRACT
BACKGROUND: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation. RESULTS: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. CONCLUSION: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.
Subject(s)
Caloric Restriction , Enzyme Activation/genetics , Models, Genetic , Signal Transduction/genetics , Sirtuins/metabolism , Animals , Enzyme Activation/drug effects , Gene Expression Profiling , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Mice , Microarray Analysis , Molecular Structure , Resveratrol , Signal Transduction/drug effects , Sirtuin 1 , Stilbenes/chemistry , Stilbenes/pharmacologySubject(s)
Proto-Oncogene Proteins c-bcl-2/metabolism , Animals , Apoptosis , Apoptosis Regulatory Proteins/metabolism , BH3 Interacting Domain Death Agonist Protein/metabolism , Bcl-2-Like Protein 11 , Membrane Proteins/metabolism , Mice , Mitochondria/metabolism , Proto-Oncogene Proteins/metabolism , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolismABSTRACT
Programmed cell death is an ordered process that is essential for the normal development and homeostasis of an organism. Dysregulation of this programmed pathway, resulting in either excess cell numbers or unscheduled cell death, underlies a number of disease states. Bcl-2 family proteins play a key role in regulating cell death and survival, and a number of studies have demonstrated their role as important regulators of cell fate in the lymphoid system. Mice that are genetically deficient or overexpress various Bcl-2 family proteins have provided important clues regarding their roles in lymphocyte development, progression of lymphoid tumors and analogous human disorders. In addition, lymphotropic viruses may trigger cell proliferation and inhibit cell death with the help of their own Bcl-2 homologues. Comparing the shared and distinct functions of viral and cellular Bcl-2-related proteins yields new insight into their fundamental mechanisms.