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Publication
Targeting I?B kinase ß in Adipocyte Lineage Cells for Treatment of Obesity and
Metabolic Dysfunctions.
Authors Helsley RN, Sui Y, Park SH, Liu Z, Lee RG, Zhu B, Kern PA, Zhou C
Submitted By Submitted Externally on 7/27/2017
Status Published
Journal Stem cells (Dayton, Ohio)
Year 2016
Date Published 7/1/2016
Volume : Pages 34 : 1883 - 95
PubMed Reference 26991836
Abstract I?B kinase ß (IKKß), a central coordinator of inflammation through activation of
nuclear factor-?B, has been identified as a potential therapeutic target for the
treatment of obesity-associated metabolic dysfunctions. In this study, we
evaluated an antisense oligonucleotide (ASO) inhibitor of IKKß and found that
IKKß ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly,
IKKß ASO also inhibited adipocyte differentiation and reduced adiposity in
high-fat (HF)-fed mice, indicating an important role of IKKß signaling in the
regulation of adipocyte differentiation. Indeed, CRISPR/Cas9-mediated genomic
deletion of IKKß in 3T3-L1 preadipocytes blocked these cells differentiating
into adipocytes. To further elucidate the role of adipose progenitor IKKß
signaling in diet-induced obesity, we generated mice that selectively lack IKKß
in the white adipose lineage and confirmed the essential role of IKKß in
mediating adipocyte differentiation in vivo. Deficiency of IKKß decreased
HF-elicited adipogenesis in addition to reducing inflammation and protected mice
from diet-induced obesity and insulin resistance. Further, pharmacological
inhibition of IKKß also blocked human adipose stem cell differentiation. Our
findings establish IKKß as a pivotal regulator of adipogenesis and suggest that
overnutrition-mediated IKKß activation serves as an initial signal that triggers
adipose progenitor cell differentiation in response to HF feeding. Inhibition of
IKKß with antisense therapy may represent as a novel therapeutic approach to
combat obesity and metabolic dysfunctions. Stem Cells 2016;34:1883-1895.






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