Biotechnology Department, College of Science, University of Baghdad, Baghdad, Iraq; Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Mol Cell Endocrinol. 2023 Jan 1;559:111809. doi: 10.1016/j.mce.2022.111809. Epub 2022 Oct 23.
An internal circadian clock regulates timing of systemic energy homeostasis. The central clock in the hypothalamic suprachiasmatic nucleus (SCN) directs local clocks in peripheral tissues such as liver, muscle, and adipose tissue to synchronize metabolism with food intake and rest/activity cycles. Aryl hydrocarbon receptor (AhR) interacts with the molecular circadian clockworks. Activation of AhR dampens rhythmic expression of core clock genes, which may lead to metabolic dysfunction. Given the importance of appropriately-timed adipose tissue function to regulation of energy homeostasis, this study focused on mechanisms by which AhR may influence clock-controlled adipose tissue activity. We hypothesized that AhR activation in adipose tissue would impair lipolysis by dampening adipose rhythms, leading to a decreased lipolysis rate during fasting, and subsequently, altered serum glucose concentrations. Levels of clock gene and lipolysis gene transcripts in mouse mesenchymal stem cells (BMSCs) differentiated into mature adipocytes were suppressed by the AhR agonist β-napthoflavone (BNF), in an AhR dependent manner. BNF altered rhythms of core clock gene and lipolysis gene transcripts in C57bl6/J mice. BNF reduced serum free fatty acids, glycerol and liver glycogen. Chromatin immunoprecipitation indicated that BNF increased binding of AhR to E-Box elements in clock gene and lipolysis gene promoters. These data establish a link between AhR activation and impaired lipolysis, specifically by altering adipose tissue rhythmicity. In response to the decreased available energy from impaired lipolysis, the body increases glycogenolysis, thereby degrading more glycogen to provide necessary energy.
内在生物钟调节全身能量稳态的时间。下丘脑视交叉上核（SCN）中的中央时钟指导肝脏、肌肉和脂肪组织等外周组织中的局部时钟与食物摄入和休息/活动周期同步。芳香烃受体（AhR）与分子生物钟相互作用。AhR 的激活会抑制核心时钟基因的节律表达，这可能导致代谢功能障碍。鉴于脂肪组织适时发挥作用对于调节能量稳态的重要性，本研究集中探讨 AhR 影响时钟控制脂肪组织活性的机制。我们假设脂肪组织中 AhR 的激活会通过抑制脂肪组织节律来削弱脂肪分解，导致禁食期间脂肪分解率降低，随后血清葡萄糖浓度发生变化。AhR 激动剂β-萘黄酮（BNF）以 AhR 依赖的方式抑制小鼠间充质干细胞（BMSC）分化为成熟脂肪细胞中时钟基因和脂肪分解基因转录本的表达。BNF 改变了 C57bl6/J 小鼠核心时钟基因和脂肪分解基因转录本的节律。BNF 降低了血清游离脂肪酸、甘油和肝糖原。染色质免疫沉淀表明 BNF 增加了 AhR 与时钟基因和脂肪分解基因启动子中 E-Box 元件的结合。这些数据确立了 AhR 激活与脂肪分解受损之间的联系，特别是通过改变脂肪组织的节律性。作为对脂肪分解受损导致的可用能量减少的反应，身体会增加糖原分解，从而降解更多的糖原以提供必要的能量。
