Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; The Second Affiliated Hospital of Zhengzhou University, People's Republic of China.
Honghui Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167528. doi: 10.1016/j.bbadis.2024.167528. Epub 2024 Oct 2.
Peroxisome proliferator-activated receptor gamma coactivators 1β (PGC1β) is essential in mitochondrial oxidative phosphorylation and alternative macrophages activation. To determine the contribution of PGC1β in obesity induced inflammation, Ppargc1b (PGC1β coding gene) myeloid conditional knockout mice (cKO) were fed with high fat diet (HFD) to examine the following effects. We found that HFD-fed cKO mice gained more fat with increased serum triglyceride (TG), low density lipoprotein (LDL), adiponectin, and leptin. Adipogenesis was stimulated while lipolysis was retarded in HFD-fed cKO mice adipose. Gluconeogenesis, lipogenesis, and fatty acid uptake were provoked while lipolysis was inhibited in HFD-fed cKO liver. Serum alanine transaminase (ALT) level, indicating fatty liver, also increased. Inflammatory cytokine including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 was elevated in cKO mice, accompanied with glucose intolerant and insulin resistance. Energy expenditure was decreased in HFD-fed cKO mice. Further evidence showed that cKO macrophages were prone to repolarize into M1 inflammatory type in vitro. In addition to mitochondrial biogenesis and oxidative respiration, PGC1β also modulated mitochondrial fission and cytosolic mitochondrial DNA (mtDNA) release, contributing to NLR family pyrin domain containing 3 (Nlrp3) inflammasome priming and activation. Treatment of mitochondrial fission inhibitor abolished the increased mRNA levels of Nlrp3 and IL-1β induced by PGC1β depletion. Nlrp3 knockdown restored the induced IL-1β mRNA expression by PGC1β deficiency. Myeloid PGC1β regulated adipocyte adipogenesis and lipolysis. PGC1β loss-of-function and mtDNA abundance correlated with obesity and diabetes. These observations uncovered the protective role of PGC1β against obesity induced systemic inflammation. Enhancing myeloid PGC1β function may be a potential strategy for the intervention of obesity and related diseases.
过氧化物酶体增殖物激活受体γ共激活因子 1β（PGC1β）在线粒体氧化磷酸化和替代型巨噬细胞激活中起关键作用。为了确定 PGC1β 在肥胖诱导的炎症中的作用，用高脂肪饮食（HFD）喂养 Ppargc1b（PGC1β 编码基因）骨髓细胞条件性敲除小鼠（cKO），以观察以下影响。我们发现，HFD 喂养的 cKO 小鼠脂肪增加更多，血清甘油三酯（TG）、低密度脂蛋白（LDL）、脂联素和瘦素水平升高。脂肪生成受到刺激，而脂肪分解受到抑制。HFD 喂养的 cKO 肝脏的糖异生、脂肪生成和脂肪酸摄取被激发，而脂肪分解受到抑制。血清丙氨酸转氨酶（ALT）水平升高，表明发生了脂肪肝。炎性细胞因子，包括肿瘤坏死因子-α（TNF-α）、IL-1β 和 IL-6，在 cKO 小鼠中升高，伴有葡萄糖不耐受和胰岛素抵抗。HFD 喂养的 cKO 小鼠的能量消耗减少。进一步的证据表明，cKO 巨噬细胞在体外易向 M1 炎症型极化。除了线粒体生物发生和氧化呼吸外，PGC1β 还调节线粒体裂变和细胞质线粒体 DNA（mtDNA）释放，有助于 Nlrp3 炎性小体的初始激活。线粒体裂变抑制剂的处理消除了 PGC1β 耗竭诱导的 Nlrp3 和 IL-1β mRNA 水平的增加。Nlrp3 敲低恢复了 PGC1β 缺陷诱导的 IL-1β mRNA 表达。骨髓细胞 PGC1β 调节脂肪细胞脂肪生成和脂肪分解。PGC1β 功能丧失和 mtDNA 丰度与肥胖和糖尿病相关。这些观察结果揭示了 PGC1β 对肥胖诱导的全身炎症的保护作用。增强骨髓细胞 PGC1β 的功能可能是肥胖及其相关疾病干预的一种潜在策略。
