Liver-restricted Repin1 deficiency improves whole-body insulin sensitivity, alters lipid metabolism, and causes secondary changes in adipose tissue in mice.
Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue and maps within a quantitative trait locus (QTL) for body weight and triglyceride (TG) levels in the rat. The QTL has further been supported as a susceptibility locus for dyslipidemia and related metabolic disorders in congenic and subcongenic rat strains. Here, we elucidated the role of Repin1 in lipid metabolism in vivo. We generated a liver-specific Repin1 knockout mouse (LRep1(-/-)) and systematically characterized the consequences of Repin1 deficiency in the liver on body weight, glucose and lipid metabolism, liver lipid patterns, and protein/mRNA expression. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved whole-body insulin sensitivity in LRep1(-/-) mice, which may be due to significantly lower TG content in the liver. Repin1 deficiency causes significant changes in potential downstream target molecules including Cd36, Pparγ, Glut2 protein, Akt phosphorylation, and lipocalin2, Vamp4, and Snap23 mRNA expression. Mice with hepatic deletion of Repin1 display secondary changes in adipose tissue function, which may be mediated by altered hepatic expression of lipocalin2 or chemerin. Our findings indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism.
Department of Medicine, University of Leipzig, Leipzig, Germany.
Matthias
M
Kern
Department of Medicine, University of Leipzig, Leipzig, Germany.
Joanna
J
Kosacka
Department of Medicine, University of Leipzig, Leipzig, Germany.
Nico
N
Hesselbarth
Department of Medicine, University of Leipzig, Leipzig, Germany.
Julia
J
Brückner
Department of Medicine, University of Leipzig, Leipzig, Germany.
John T
JT
Heiker
IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
Gesine
G
Flehmig
Department of Laboratory Animal Science, University of Greifswald, Karlsburg, Germany.
Ingrid
I
Klöting
IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
Peter
P
Kovacs
Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
Madlen
M
Matz-Soja
Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
Rolf
R
Gebhardt
Interdisciplinary Center for Clinical Research, Core Unit DNA Technologies, University of Leipzig, Leipzig, Germany.
Knut
K
Krohn
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Susanne
S
Sales
Institute for Experimental Surgery, Rostock University Medical School, Rostock, Germany.
Kerstin
K
Abshagen
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Andrej
A
Shevchenko
Department of Medicine, University of Leipzig, Leipzig, Germany IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
Michael
M
Stumvoll
Department of Medicine, University of Leipzig, Leipzig, Germany IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
Matthias
M
Blüher
Department of Medicine, University of Leipzig, Leipzig, Germany IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany nora.kloeting@medizin.uni-leipzig.de.
Nora
N
Klöting
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology
D004268:DNA-Binding Proteins; D007328:Insulin; D016601:RNA-Binding Proteins; C552723:Repin1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose