Kang Gi-Sue, Kim Young-Eun, Oh Ho Rim, Jo Hye-Ju, Bok Seoyeon, Jeon Yoon Kyung, Cheon Gi Jeong, Roh Tae-Young, Chang Young-Tae, Park Do Joong, Ahn G-One
College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea.
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Korea.
Lab Anim Res. 2024 Oct 30;40(1):37. doi: 10.1186/s42826-024-00224-4.
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.
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.
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.
解偶联蛋白1（UCP1）是一种位于线粒体内膜的质子解偶联剂，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烈表达，但最近的证据表明，白色脂肪细胞在某些情况下，如寒冷或β-肾上腺素能受体刺激下，也能表达UCP1，使其获得棕色脂肪细胞样特征，从而成为“米色”脂肪细胞。
在本研究中，我们报告UCP1可以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，且这一过程不需要寒冷刺激或β-肾上腺素能受体激活。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能够免受饮食诱导的肥胖影响，并且在寒冷挑战时表现出更好的产热耐受性。从喂食高脂饮食的这些小鼠的白色脂肪组织（WAT）中分离出的ATM表现出显著更高的M2极化、糖酵解减少、线粒体功能和乙酰辅酶A水平增加，同时Ucp1、过氧化物酶体增殖物激活受体γ共激活因子-1a以及其他参与组蛋白乙酰化的基因表达增加。与Ucp1基因表达增加一致，这些ATM产生了大量热量，介导共培养的脂肪细胞的脂解作用，释放出游离脂肪酸。用乙酸盐（一种乙酰辅酶A合成的底物）处理ATM能够促进野生型或Hif-1α缺陷型巨噬细胞的产热，但对UCP1缺陷型巨噬细胞无效，这表明UCP1是巨噬细胞产热所必需的。最后，我们观察到WAT中表达UCP1的ATM数量与人类个体的体重指数之间存在显著的负相关。
表达UCP1的ATM产生热量以介导脂肪细胞的脂解作用，表明这可能是一种治疗和预防饮食诱导肥胖的新策略。
