Burgess Angela P H, Vanella Luca, Bellner Lars, Gotlinger Katherine, Falck John R, Abraham Nader G, Schwartzman Michal L, Kappas Attallah
Department of Physiology and Pharmacology, University of Toledo, Toledo, USA.
Cell Physiol Biochem. 2012;29(1-2):99-110. doi: 10.1159/000337591. Epub 2012 Mar 1.
BACKGROUND/AIMS: HO-1 and EETs are functionally linked and their interactions influence body weight, insulin sensitivity, and serum levels of inflammatory cytokines in metabolic syndrome phenotype of HO-2 null mice. The HO-2 isozyme is essential for regulating physiological levels of ROS. Recent studies have suggested a potential role of EET in modifying adipocyte differentiation through up-regulation of HO-1-adiponectin-AkT signaling in human mesenchymal stem cells (MSCs). Our aim was to examine the consequences of HO deficiency on MSC-derived adipogenesis in vitro using MSC derived from HO-2 null and WT mice in vivo.
Four-month-old HO-2 null (HO-2(-/-)) and B6/129SF2/J (WT) mice were divided into three groups (four mice/group): WT, HO-2(-/-), and HO-2(-/-) +CoPP. Adipogenesis was performed on purified MSC-derived adipocytes cultured in adipogenic differentiation media and an EET-agonist was added every 3 days.
HO-2 depletion of MSC adipocytes resulted in increased adipogenesis (p<0.01) and increased levels of inflammatory cytokines including (TNF)-alpha (p<0.05), (MCP)-1 (p<0.05), and (IL-1)-beta (p<0.05). These results were accompanied by decreases in HO-1 (p<0.05) and subsequently EET and HO activity (p<0.05). Up-regulation of HO-1 resulted in decreased MSC-derived adipocyte differentiation, decreased production of TNF-alpha and MCP-1 and increased levels of adiponectin (p<0.05). Cyp2J5 (p<0.05), HO-1 (p<0.05), and adiponectin mRNA levels (p<0.05) were also decreased in visceral adipose tissue isolated from HO-2 null compared to WT mice. EET agonist stimulation of MSC adipocytes derived from HO-2 null mice yielded similar results.
Increased levels of EET and HO-1 are essential for protection against the adverse effects of adipocyte hypertrophy and the ensuing metabolic syndrome. These results offer a portal into therapeutic approaches for the prevention of the metabolic syndrome.
背景/目的：血红素加氧酶-1（HO-1）和环氧二十碳三烯酸（EETs）在功能上相互关联，它们的相互作用会影响HO-2基因敲除小鼠代谢综合征表型中的体重、胰岛素敏感性以及炎性细胞因子的血清水平。HO-2同工酶对于调节活性氧（ROS）的生理水平至关重要。最近的研究表明，EET通过上调人间充质干细胞（MSCs）中HO-1-脂联素-Akt信号通路，在调节脂肪细胞分化方面具有潜在作用。我们的目的是利用体内来源于HO-2基因敲除小鼠和野生型（WT）小鼠的MSCs，研究HO缺乏对体外MSCs来源的脂肪生成的影响。
将4个月大的HO-2基因敲除（HO-2(-/-)）小鼠和B6/129SF2/J（WT）小鼠分为三组（每组4只小鼠）：WT组、HO-2(-/-)组和HO-2(-/-)+钴原卟啉（CoPP）组。对在脂肪生成分化培养基中培养的纯化MSCs来源的脂肪细胞进行脂肪生成实验，并每3天添加一次EET激动剂。
MSCs脂肪细胞中HO-2的缺失导致脂肪生成增加（p<0.01），炎性细胞因子水平升高，包括肿瘤坏死因子-α（TNF-α，p<0.05）、单核细胞趋化蛋白-1（MCP-1，p<0.05）和白细胞介素-1β（IL-1β，p<0.05）。这些结果伴随着HO-1水平降低（p<0.05），随后EET和HO活性降低（p<0.05）。HO-1的上调导致MSCs来源的脂肪细胞分化减少，TNF-α和MCP-1的产生减少，脂联素水平升高（p<0.05）。与WT小鼠相比，从HO-2基因敲除小鼠分离的内脏脂肪组织中细胞色素P450 2J5（Cyp2J5，p<0.05）、HO-1（p<0.05）和脂联素mRNA水平也降低（p<0.05）。EET激动剂刺激HO-2基因敲除小鼠来源的MSCs脂肪细胞也产生了类似的结果。
EET和HO-1水平升高对于预防脂肪细胞肥大的不良影响及随之而来的代谢综合征至关重要。这些结果为预防代谢综合征的治疗方法提供了一个切入点。
