RAP1 protects from obesity through its extratelomeric role regulating gene expression

2015-01-13

"C:\Users\kurtw_000\Box Sync\DocDR\2014\02-07-2014d0952\RAP1 protects from obesity through its extratelomeric role regulating gene expression.pdf"

Abstract
RAP1 is part of shelterin, the protective complex at telomeres. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the nontelomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knockout mouse. These mice show early onset of obesity, which is more severe in females than in males. Rap1-deficient mice show accumulation of abdominal fat, hepatic steatosis, and high-fasting plasma levels of insulin, glucose, cholesterol, and alanine aminotransferase. Gene expression analyses of liver and visceral white fat from Rap1-deficient mice before the onset of obesity show deregulation of metabolic programs, including fatty acid, glucose metabolism, and PPARa signaling. We identify Ppara and Pgc1a as key factors affected by Rap1 deletion in the liver. We show that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings reveal a role for a telomere-binding protein in the regulation of metabolism.

Some notes
-CNIO and NIH paper
-Cell journal
- we generated a RAP1 whole-body knockout
mouse.
-These mice show early onset of obesity,
which is more severe in females than in males
-These ?ndings reveal a role for
a telomere-binding protein in the regulation of
metabolism.
-Generation of Whole-Body Rap1 -De?cient Mice
-Rap1 -De?cient Mice Are Viable but Show an Early Onset
of Obesity
-Rap1 -De?cient Mice Accumulate More Fat in Visceral
Tissues and Show Signs of Liver Steatosis and
In?ammation
-Rap1 -De?cient Mice Are Glucose Resistant and Show
Some Signs of Metabolic Syndrome
-High-Fat Diet Further Aggravates Obesity and Diabetes
in Rap1 -De?cient Females
-Metabolic Alterations in Rap1 -De?cient Tissues Occur
in the Absence of Changes in Telomere Length and in
the Absence of Telomere Damage
- Enhanced Weight Gain and Glucose Resistance in Rap1 Null Females Subjected to a HFD
-RAP1 De?ciency Affects Metabolic Transcriptional
Networks before the Onset of Obesity
-Decreased mRNA and Protein Expression of Ppara and
Pgc1a in Rap1 -De?cient Livers
-Defective Expression of PPAR a Target Genes in Rap1 -
De?cient Livers upon Fasting
-RAP1 Binds to Ppara and Pgc1a Loci
-RAP1 Regulates Ppara and Pgc1a Transcription
-In conclusion, we demonstrate here that RAP1 serves as a
transcriptional regulator that controls the capacity of down-
stream metabolic pathways critical for metabolic maturation
-knockout mice
-ELISA
-gene expression analysis
-Luciferase and ChIP Assays

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