PMID- 28579235 OWN - NLM STAT- MEDLINE DCOM- 20171019 LR - 20180919 IS - 1388-1981 (Print) IS - 1388-1981 (Linking) VI - 1862 IP - 9 DP - 2017 Sep TI - Haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice. PG - 946-957 LID - S1388-1981(17)30103-8 [pii] LID - 10.1016/j.bbalip.2017.05.012 [doi] AB - AIMS: To investigate whether haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice. METHODS AND RESULTS: Experiments were performed using irradiated LDL receptor-deficient (LDLR(-/-)) mice with marrow from either TLR4-deficient (TLR4(-/-)) or age-matched wild-type (WT) mice. After 12 weeks of being fed a high-cholesterol diet, TLR4(-/-)-->LDLR(-/-) mice developed fewer atherosclerotic lesions in the aorta compared to WT-->LDLR(-/-) mice. This effect was associated with an increase in multilocular lipid droplets and mitochondria in perivascular adipose tissue (PVAT). Immunofluorescence analysis confirmed that there was an increase in capillary density and M2 macrophage infiltration, accompanied by a decrease in tumour necrosis factor (TNF)-alpha expression in the localized PVAT of TLR4(-/-)-->LDLR(-/-) mice. In vitro studies indicated that bone marrow-derived macrophages (BMDMs) from WT mice demonstrated an M1-like phenotype and expression of inflammatory cytokines induced by palmitate. These effects were attenuated in BMDMs isolated from TLR4(-/-) mice. Furthermore, brown adipocytes incubated with conditioned medium (CM) derived from palmitate-treated BMDMs, exhibited larger and more unilocular lipid droplets, and reduced expression of brown adipocyte-specific markers and perilipin-1 compared to those observed in brown adipocytes exposed to CM from palmitate-treated BMDMs of TLR4(-/-) mice. This decreased potency was primarily due to TNF-alpha, as demonstrated by the capacity of the TNF-alpha neutralizing antibody to reverse these effects. CONCLUSIONS: These results suggest that haematopoietic-specific deletion of TLR4 promotes PVAT homeostasis, which is involved in reducing macrophage-induced TNF-alpha secretion and increasing mitochondrial biogenesis in brown adipocytes. CI - Copyright (c) 2017. Published by Elsevier B.V. FAU - Liu, Penghao AU - Liu P AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China. FAU - Huang, Gaojian AU - Huang G AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. FAU - Cao, Zhiyong AU - Cao Z AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Department of General Internal Medicine, Branch of 411 Hospital of People's Liberation Army, Shanghai 200433, China. FAU - Xie, Qihai AU - Xie Q AD - Department of Cardiology, Shanghai Jia Ding District Central Hospital, Shanghai 201800, China. FAU - Wei, Tong AU - Wei T AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. FAU - Huang, Chenglin AU - Huang C AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. FAU - Li, Qun AU - Li Q AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. FAU - Sun, Mengwei AU - Sun M AD - Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai 200030, China. FAU - Shen, Weili AU - Shen W AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: wlshen@sibs.ac.cn. FAU - Gao, Pingjin AU - Gao P AD - State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170601 PL - Netherlands TA - Biochim Biophys Acta Mol Cell Biol Lipids JT - Biochimica et biophysica acta. Molecular and cell biology of lipids JID - 101731727 RN - 0 (Biomarkers) RN - 0 (Perilipin-1) RN - 0 (Receptors, LDL) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Adipose Tissue, Brown/*metabolism MH - Animals MH - Atherosclerosis/*metabolism MH - Biomarkers/metabolism MH - Bone Marrow/metabolism MH - Inflammation/*metabolism MH - Lipid Droplets/metabolism MH - Macrophages/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Perilipin-1/metabolism MH - Receptors, LDL/metabolism MH - Toll-Like Receptor 4/*metabolism MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Brown adipose tissue OT - Mitochondrion OT - PVAT OT - TLR4 EDAT- 2017/06/06 06:00 MHDA- 2017/10/20 06:00 CRDT- 2017/06/06 06:00 PHST- 2017/01/08 00:00 [received] PHST- 2017/05/20 00:00 [revised] PHST- 2017/05/29 00:00 [accepted] PHST- 2017/06/06 06:00 [pubmed] PHST- 2017/10/20 06:00 [medline] PHST- 2017/06/06 06:00 [entrez] AID - S1388-1981(17)30103-8 [pii] AID - 10.1016/j.bbalip.2017.05.012 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):946-957. doi: 10.1016/j.bbalip.2017.05.012. Epub 2017 Jun 1.