过氧化物酶体增殖物激活受体 γ 共激活剂 1β (PGC1β) 在线粒体氧化磷酸化和替代性巨噬细胞激活中至关重要。为了确定 PGC1β 在肥胖引起的炎症中的作用，用高脂饮食 (HFD) 喂养 Ppargc1b（PGC1β 编码基因）骨髓条件敲除小鼠 (cKO)，以检查以下效果。我们发现，高脂饮食喂养的 cKO 小鼠脂肪增加，血清甘油三酯 (TG)、低密度脂蛋白 (LDL)、脂联素和瘦素增加。在 HFD 喂养的 cKO 小鼠脂肪中，脂肪生成受到刺激，而脂肪分解则受到延迟。在 HFD 喂养的 cKO 肝脏中，糖异生、脂肪生成和脂肪酸摄取被激发，而脂肪分解则受到抑制。表明脂肪肝的血清丙氨酸转氨酶（ALT）水平也升高。 cKO小鼠中炎症细胞因子包括肿瘤坏死因子-α（TNF-α）、IL-1β和IL-6升高，并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巨噬细胞在体外易于复极化为M1炎症型。除了线粒体生物合成和氧化呼吸之外，PGC1β 还调节线粒体裂变和胞质线粒体 DNA (mtDNA) 释放，有助于 NLR 家族 Pyrin 结构域 3 (Nlrp3) 炎性体的启动和激活。线粒体裂变抑制剂的治疗消除了 PGC1β 耗竭引起的 Nlrp3 和 IL-1β mRNA 水平的增加。 Nlrp3 敲低可恢复 PGC1β 缺陷诱导的 IL-1β mRNA 表达。髓样 PGC1β 调节脂肪细胞的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 对肥胖引起的全身炎症的保护作用。增强骨髓 PGC1β 功能可能是干预肥胖及相关疾病的潜在策略。版权所有 © 2024。由 Elsevier B.V. 出版。

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.Copyright © 2024. Published by Elsevier B.V.