| First Author | Helsley RN | Year | 2016 |
| Journal | Stem Cells | Volume | 34 |
| Issue | 7 | Pages | 1883-95 |
| PubMed ID | 26991836 | Mgi Jnum | J:238113 |
| Mgi Id | MGI:5818118 | Doi | 10.1002/stem.2358 |
| Citation | Helsley RN, et al. (2016) Targeting IkappaB kinase beta in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions. Stem Cells 34(7):1883-95 |
| abstractText | IkappaB kinase beta (IKKbeta), a central coordinator of inflammation through activation of nuclear factor-kappaB, 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 IKKbeta and found that IKKbeta ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly, IKKbeta ASO also inhibited adipocyte differentiation and reduced adiposity in high-fat (HF)-fed mice, indicating an important role of IKKbeta signaling in the regulation of adipocyte differentiation. Indeed, CRISPR/Cas9-mediated genomic deletion of IKKbeta in 3T3-L1 preadipocytes blocked these cells differentiating into adipocytes. To further elucidate the role of adipose progenitor IKKbeta signaling in diet-induced obesity, we generated mice that selectively lack IKKbeta in the white adipose lineage and confirmed the essential role of IKKbeta in mediating adipocyte differentiation in vivo. Deficiency of IKKbeta decreased HF-elicited adipogenesis in addition to reducing inflammation and protected mice from diet-induced obesity and insulin resistance. Further, pharmacological inhibition of IKKbeta also blocked human adipose stem cell differentiation. Our findings establish IKKbeta as a pivotal regulator of adipogenesis and suggest that overnutrition-mediated IKKbeta activation serves as an initial signal that triggers adipose progenitor cell differentiation in response to HF feeding. Inhibition of IKKbeta with antisense therapy may represent as a novel therapeutic approach to combat obesity and metabolic dysfunctions. Stem Cells 2016;34:1883-1895. |
