LMO3 reprograms visceral adipocyte metabolism during obesity.
LMO3 reprograms visceral adipocyte metabolism during obesity.
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DOI：
10.1007/s00109-021-02089-9
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Bilban M
中科院分区：
文献类型：
--
作者：
Wagner G;Fenzl A;Lindroos-Christensen J;Einwallner E;Husa J;Witzeneder N;Rauscher S;Gröger M;Derdak S;Mohr T;Sutterlüty H;Klinglmüller F;Wolkerstorfer S;Fondi M;Hoermann G;Cao L;Wagner O;Kiefer FW;Esterbauer H;Bilban M
肥胖和体脂分布是2型糖尿病和代谢综合征发生的重要危险因素。有证据表明，这种风险与不同脂肪库中脂肪细胞行为的内在差异有关。我们最近在人类成熟内脏脂肪细胞中鉴定了LIM结构域仅3（LMO 3）;然而，其在这些细胞中的功能目前尚不清楚。本研究的目的是确定LMO 3依赖性途径在肥胖期间成熟脂肪细胞关键功能调节中的潜在参与。基于最近工程化的杂合rAAV血清型Rec 2显示出有效地抑制棕色脂肪组织（BAT）和白色脂肪组织（WAT），我们将YFP或Lmo 3递送至高脂饮食（HFD）的C57 B16/J小鼠的附睾WAT（eWAT）。10周后评估eWAT转导对代谢参数的影响。为了进一步确定LMO 3在胰岛素刺激的葡萄糖摄取、胰岛素信号传导、脂肪细胞生物能量学以及内分泌功能中的作用，在3 T3-L1脂肪细胞和新分化的人原代成熟脂肪细胞中进行实验，所述脂肪细胞和新分化的人原代成熟脂肪细胞分别被工程化以瞬时获得或丧失LMO 3表达。eWAT的AAV转导导致在HFD喂养的10周的过程中在脂肪细胞级分中特异性地强烈且稳定的Lmo 3表达。eWAT中的LMO 3表达显著改善了饮食诱导的肥胖症中的胰岛素敏感性和健康的内脏脂肪组织扩张，这与血清脂联素增加有关。在体外，LMO 3在3 T3-L1脂肪细胞中的表达增加了PPARγ转录活性、胰岛素刺激的GLUT 4易位和葡萄糖摄取，以及除了脂肪酸氧化之外的线粒体氧化能力。从机制上讲，LMO 3诱导了LMO 3增强葡萄糖摄取和线粒体氧化基因表达所需的PPARγ辅助调节因子Ncoa 1。在人成熟脂肪细胞中，LMO 3过表达促进，而LMO 3沉默抑制线粒体氧化能力。内脏脂肪组织中的LMO 3表达调节在肥胖期间保持脂肪组织功能的多个基因，例如葡萄糖代谢、胰岛素敏感性、线粒体功能和脂联素分泌。这些基因表达变化与增加的PPARγ活性和Ncoa 1表达一起促进胰岛素诱导的GLUT 4易位、葡萄糖摄取以及线粒体氧化能力增加，限制HFD诱导的脂肪功能障碍。这些数据增加了LMO 3作为一种新的调节剂，在肥胖期间改善内脏脂肪组织功能。LMO 3在体内增加有益的内脏脂肪组织扩张和胰岛素敏感性。LMO 3增加脂肪细胞中的葡萄糖摄取和氧化线粒体活性。LMO 3增加核辅激活因子1（Ncoa 1）。LMO 3增强葡萄糖摄取和线粒体基因表达需要Ncoa 1。在线版本包含补充材料，可通过10.1007/s 00109 -021-02089-9获得。
Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1. The online version contains supplementary material available at 10.1007/s00109-021-02089-9.
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影响因子：
29
作者：
Jeffery E;Wing A;Holtrup B;Sebo Z;Kaplan JL;Saavedra-Peña R;Church CD;Colman L;Berry R;Rodeheffer MS
通讯作者：
Rodeheffer MS
肉碱棕榈酰转移酶 1A 通过抑制 c-Jun N 末端激酶来预防脂肪酸诱导的脂肪细胞功能障碍
影响因子：
4.1
作者：
Gao, Xuefei;Li, Kuai;Wu, Donghai
通讯作者：
Wu, Donghai
影响因子：
15.9
作者：
Combs, TP;Berg, AH;Rossetti, L
通讯作者：
Rossetti, L
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM