title: Targeting IκB kinase β in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions.
abstract: IκB kinase β (IKKβ), a central coordinator of inflammation through activation of nuclear factor-κB, 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 IKKβ and found that IKKβ ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly, IKKβ ASO also inhibited adipocyte differentiation and reduced adiposity in high-fat (HF)-fed mice, indicating an important role of IKKβ signaling in the regulation of adipocyte differentiation. Indeed, CRISPR/Cas9-mediated genomic deletion of IKKβ in 3T3-L1 preadipocytes blocked these cells differentiating into adipocytes. To further elucidate the role of adipose progenitor IKKβ signaling in diet-induced obesity, we generated mice that selectively lack IKKβ in the white adipose lineage and confirmed the essential role of IKKβ in mediating adipocyte differentiation in vivo. Deficiency of IKKβ decreased HF-elicited adipogenesis in addition to reducing inflammation and protected mice from diet-induced obesity and insulin resistance. Further, pharmacological inhibition of IKKβ also blocked human adipose stem cell differentiation. Our findings establish IKKβ as a pivotal regulator of adipogenesis and suggest that overnutrition-mediated IKKβ activation serves as an initial signal that triggers adipose progenitor cell differentiation in response to HF feeding. Inhibition of IKKβ with antisense therapy may represent as a novel therapeutic approach to combat obesity and metabolic dysfunctions. Stem Cells 2016;34:1883-1895.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Helsley
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Sui
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Zun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Medicine, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kern
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.|Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Zhou
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D004032:Diet; D005234:Fatty Liver / Q000473:pathology; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D007328:Insulin; D016376:Oligonucleotides, Antisense; D051550:I-kappa B Kinase
keywords: Adipogenesis; Adipose stem cells; Antisense oligonucleotide; IκB kinase β; Obesity