한빛사논문
- 조회353
전남대학교 약학대학
Hafiz Muhammad Ahmad Javaid a, Eun Ko b,1, Esther Jin Joo c, Soon Hyo Kwon d, Jong-Hwan Park e, Sooim Shin b,f, Kae Won Cho c, Joo Young Huh a
aCollege of Pharmacy, Chonnam National University, Gwangju, Republic of Korea
bDepartment of Bioengineering and Biotechnology, College of Engineering, Chonnam National University, Gwangju 61186, Republic of Korea
cSoonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea
dDivision of Nephrology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea
eCollege of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea
fInterdisciplinary Program of Bioenergy and Biomaterials Graduate School, College of Engineering, Chonnam National University, Gwangju 61186, Republic of Korea
1Present address: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.
Corresponding author : Joo Young Huh
Abstract
Background and aims: Obesity is a state of chronic low-grade systemic inflammation. Recent studies showed that NLRP3 inflammasome initiates metabolic dysregulation in adipose tissues, primarily through activation of adipose tissue infiltrated macrophages. However, the mechanism of NLRP3 activation and its role in adipocytes remains elusive. Therefore, we aimed to examine the activation of TNFα-induced NLRP3 inflammasome in adipocytes and its role on adipocyte metabolism and crosstalk with macrophages.
Methods: The effect of TNFα on adipocyte NLRP3 inflammasome activation was measured. Caspase-1 inhibitor (Ac-YVAD-cmk) and primary adipocytes from NLRP3 and caspase-1 knockout mice were utilized to block NLRP3 inflammasome activation. Biomarkers were measured by using real-time PCR, western blotting, immunofluorescence staining, and enzyme assay kits. Conditioned media from TNFα-stimulated adipocytes was used to establish the adipocyte-macrophage crosstalk. Chromatin immunoprecipitation assay was used to identify the role of NLRP3 as a transcription factor. Mouse and human adipose tissues were collected for correlation analysis.
Results: TNFα treatment induced NLRP3 expression and caspase-1 activity in adipocytes, partly through autophagy dysregulation. The activated adipocyte NLRP3 inflammasome participated in mitochondrial dysfunction and insulin resistance, as evidenced by the amelioration of these effects in Ac-YVAD-cmk treated 3T3-L1 cells or primary adipocytes isolated from NLRP3 and caspase-1 knockout mice. Particularly, the adipocyte NLRP3 inflammasome was involved in glucose uptake regulation. Also, TNFα induced expression and secretion of lipocalin 2 (Lcn2) in a NLRP3-dependent manner. NLRP3 could bind to the promoter and transcriptionally regulate Lcn2 in adipocytes. Treatment with adipocyte conditioned media revealed that adipocyte-derived Lcn2 was responsible for macrophage NLRP3 inflammasome activation, working as a second signal. Adipocytes isolated from high-fat diet mice and adipose tissue from obese individuals showed a positive correlation between NLRP3 and Lcn2 gene expression.
Conclusions: This study highlights the importance of adipocyte NLRP3 inflammasome activation and novel role of TNFα-NLRP3-Lcn2 axis in adipose tissue. It adds rational for the current development of NLRP3 inhibitors for treating obesity-induced metabolic diseases.
논문정보
- Research article
- 2023년 05월 (BRIC 등록일 2023-05-18)
- 국내 연구진
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