Targeting IκB kinase β in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions

Stem Cells. 2016 Jul;34(7):1883-95. doi: 10.1002/stem.2358. Epub 2016 Mar 28.


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.

Keywords: Adipogenesis; Adipose stem cells; Antisense oligonucleotide; IκB kinase β; Obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipocytes / pathology*
  • Adipogenesis / drug effects
  • Animals
  • Cell Lineage* / drug effects
  • Diet
  • Fatty Liver / pathology
  • Gene Deletion
  • Gene Knockdown Techniques
  • Humans
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / metabolism*
  • Insulin / pharmacology
  • Male
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / pathology
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy*
  • Obesity / drug therapy*
  • Obesity / pathology
  • Oligonucleotides, Antisense / pharmacology
  • Stem Cells / drug effects
  • Stem Cells / metabolism


  • Insulin
  • Oligonucleotides, Antisense
  • I-kappa B Kinase