缺氧诱导因子-1α缺陷的脂肪组织巨噬细胞产生热量,通过解偶联蛋白-1介导白色脂肪组织的脂肪分解。

IF 2.7 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Gi-Sue Kang, Young-Eun Kim, Ho Rim Oh, Hye-Ju Jo, Seoyeon Bok, Yoon Kyung Jeon, Gi Jeong Cheon, Tae-Young Roh, Young-Tae Chang, Do Joong Park, G-One Ahn
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引用次数: 0

摘要

背景:解偶联蛋白1(UCP1)是位于线粒体膜上的质子解偶联剂,通常参与棕色脂肪组织的产热过程。尽管已知 UCP1 在棕色脂肪细胞中强表达,但最近的证据表明,白色脂肪细胞在某些情况下也能表达 UCP1,如冷或 β 肾上腺素能受体刺激,使其获得棕色脂肪细胞样特征,从而成为 "米色 "脂肪细胞:在这项研究中,我们报告了 UCP1 可在缺乏功能性缺氧诱导因子-1(HIF-1)的脂肪组织巨噬细胞(ATM)中表达,而这并不需要冷或 β 肾上腺素能受体的激活。通过使用髓系特异性 Hif-1α 基因敲除(KO)小鼠,我们观察到这些小鼠受到饮食诱导的肥胖的保护,并在寒冷挑战时表现出更好的热耐受性。从高脂饮食喂养的这些小鼠的白色脂肪组织(WAT)中分离出的ATM表现出明显更高的M2极化、糖酵解减少、线粒体功能和乙酰-CoA水平增加,以及Ucp1、过氧化物酶体增殖激活受体-γ共激活剂-1a和其他参与组蛋白乙酰化的物质的表达增加。与 Ucp1 基因表达的增加相一致的是,这些 ATM 产生了大量的热量,介导了共培养脂肪细胞的脂肪分解,释放出游离脂肪酸。用乙酸盐(乙酰-CoA合成的底物)处理ATM能提高野生型或Hif-1α缺陷型巨噬细胞的产热,但不能提高UCP1缺陷型巨噬细胞的产热,这表明UCP1是巨噬细胞产热的必要条件。最后,我们观察到,WAT 中表达 UCP1 的 ATM 的数量与人类的体重指数之间存在显著的反相关关系:结论:表达 UCP1 的 ATM 能产生热量以介导脂肪细胞的脂肪分解,这表明它可以成为治疗和预防饮食引起的肥胖症的一种新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hypoxia-inducible factor-1α-deficient adipose-tissue macrophages produce the heat to mediate lipolysis of white adipose tissue through uncoupling protein-1.

Background: Uncoupling protein 1 (UCP1) is a proton uncoupler located across the mitochondrial membrane generally involved in thermogenesis of brown adipose tissues. Although UCP1 is known to be strongly expressed in brown adipocytes, recent evidence suggest that white adipocytes can also express UCP1 under certain circumstances such as cold- or β-adrenergic receptor-stimulation, allowing them to acquire brown adipocyte-like features thereby becoming 'beige' adipocytes.

Results: In this study, we report that UCP1 can be expressed in adipose-tissue macrophages (ATM) lacking functional hypoxia-inducible factor-1 (HIF-1) and this does not require cold- nor β-adrenergic receptor activation. By using myeloid-specific Hif-1α knockout (KO) mice, we observed that these mice were protected from diet-induced obesity and exhibited an improved thermogenic tolerance upon cold challenge. ATM isolated from white adipose tissues (WAT) of these mice fed with high fat diet exhibited significantly higher M2-polarization, decreased glycolysis, increased mitochondrial functions and acetyl-CoA levels, along with increased expression of Ucp1, peroxisome proliferator activated receptor-gamma co-activator-1a, and others involved in histone acetylation. Consistent with the increased Ucp1 gene expression, these ATM produced a significant amount of heat mediating lipolysis of co-cultured adipocytes liberating free fatty acid. Treating ATM with acetate, a substrate for acetyl-CoA synthesis was able to boost the heat production in wild-type or Hif-1α-deficient but not UCP1-deficient macrophages, indicating that UCP1 was necessary for the heat production in macrophages. Lastly, we observed a significant inverse correlation between the number of UCP1-expressing ATM in WAT and the body mass index of human individuals.

Conclusions: UCP1-expressing ATM produce the heat to mediate lipolysis of adipocytes, indicating that this can be a novel strategy to treat and prevent diet-induced obesity.

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CiteScore
4.40
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32
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