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Targeting I?B kinase ? in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions.

ABSTRACT: I?B kinase ? (IKK?), 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 IKK? and found that IKK? ASO ameliorated diet-induced metabolic dysfunctions in mice. Interestingly, IKK? ASO also inhibited adipocyte differentiation and reduced adiposity in high-fat (HF)-fed mice, indicating an important role of IKK? signaling in the regulation of adipocyte differentiation. Indeed, CRISPR/Cas9-mediated genomic deletion of IKK? in 3T3-L1 preadipocytes blocked these cells differentiating into adipocytes. To further elucidate the role of adipose progenitor IKK? signaling in diet-induced obesity, we generated mice that selectively lack IKK? in the white adipose lineage and confirmed the essential role of IKK? in mediating adipocyte differentiation in vivo. Deficiency of IKK? decreased HF-elicited adipogenesis in addition to reducing inflammation and protected mice from diet-induced obesity and insulin resistance. Further, pharmacological inhibition of IKK? also blocked human adipose stem cell differentiation. Our findings establish IKK? as a pivotal regulator of adipogenesis and suggest that overnutrition-mediated IKK? activation serves as an initial signal that triggers adipose progenitor cell differentiation in response to HF feeding. Inhibition of IKK? with antisense therapy may represent as a novel therapeutic approach to combat obesity and metabolic dysfunctions. Stem Cells 2016;34:1883-1895.

SUBMITTER: Helsley RN

PROVIDER: S-EPMC4931966 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Helsley Robert N RN Sui Yipeng Y Park Se-Hyung SH Liu Zun Z Lee Richard G RG Zhu Beibei B Kern Philip A PA Zhou Changcheng C

Stem cells (Dayton, Ohio) 20160328 7

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, indica ...[more]

PMID: 26991836

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Project description:AimsThe association of strictly defined metabolic healthy obese (MHO) with subclinical cardiac function was unclear. Our study aims to examine the role of MHO in subclinical cardiac dysfunction in a Chinese population.Methods and resultsThe study subjects were recruited from Danyang from 2017 to 2019. Obesity was defined by body mass index (BMI) categories (normal weight, overweight and obesity). Metabolic health was strictly defined as having neither any of the guidelines recommended metabolic syndrome components nor insulin resistance. Thus, subjects were grouped by BMI categories and metabolic health status as six groups. Preclinical systolic (global longitudinal strain [GLS]) and diastolic function were assessed by 2D speckle tracking, and transmitral and tissue Doppler imaging, respectively. The 2757 participants (mean age ± standard deviation, 52.7 ± 11.7 years) included 1613 (58.5%) women, 999 (36.2%) obese, 2080 (75.4%) metabolically unhealthy and 93 (3.4%) MHO participants. After adjustment for covariates, the trend was similar for left ventricular (LV) ejection fraction (Ptrend ≥ 0.07) but significantly worse for GLS, e' and E/e' (Ptrend ≤ 0.02) across the six groups or passing from normal weight to obese individuals irrespective of metabolic status. MHO participants had lower GLS (20.4 vs. 21.4%) and e' (9.6 vs. 10.6 cm/s) compared with controls (P < 0.0001) but had similar GLS (P = 0.47) compared with metabolically unhealthy obese (MUO). Regardless of obesity status, metabolically unhealthy participants had worse diastolic function compared with their metabolically healthy counterparts (P ≤ 0.0004). Compared with controls, MHO individuals were at higher risk of subclinical LV systolic dysfunction (OR = 3.44, 95% CI = 1.25-9.49, P = 0.02). These results were robust to sensitivity analysis.ConclusionsMHO was substantially associated with worse subclinical systolic function although early diastolic dysfunction seemed to be more accentuated in MUO.

Dataset Information

Targeting I?B kinase ? in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions.

Publications

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

Similar Datasets

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