Definition of central and cellular effects of thyroid hormones on white adipose tissue browning

给哺乳动物服用甲状腺激素(TH)会导致基础代谢率和产热增加。我们以前的人类研究表明，作为产热中心的蝙蝠的活动受到TH的影响。此外，使用高、低和正常甲状腺小鼠的小鼠模型，我们发现有证据表明TH可以诱导白色脂肪储存库中棕色脂肪细胞的出现。对白色脂肪组织中巨噬细胞的分析首次证明了TH在诱导交替激活的巨噬细胞中的作用，在目前的研究中，巨噬细胞与白色脂肪组织的褐化密切相关。因此，我们假设TH启动和调节Wat的褐变。这个项目的主要目的是确定最终导致TH诱导白色脂肪组织褐变的潜在机制。这将在以下三个针对具体目标的子项目中进行测试：(1)TH对Wat褐变的中枢和细胞影响的区分；(Ii)利用PET/MRI表征甲亢WAT中棕色脂肪细胞的代谢活动；(Iii)定义TH在交替激活的巨噬细胞诱导的产热中的作用。从长远来看，TH对白色脂肪组织褐变的刺激作用可能被转化为一种提高能量消耗的有效治疗方法。

Administration of thyroid hormones (TH) to mammals leads to an increase in basal metabolic rate and thermogenesis. Our previous human study demonstrates that the activity of BAT, which is the central place for thermogenesis, is influenced by TH. Furthermore, using a mouse model of hyper-, hypo-, and euthyroid mice, we found evidence that TH induce the occurrence of brown adipocytes in white adipose depots. The analysis of in white adipose tissue residing macrophages gave first evidence for a role of TH in the induction of alternatively activated macrophages, which in current studies are discussed to be closely intertwined with browning of white adipose tissues. Thus, we hypothesize that TH initiate and regulate browning of WAT. The main aim of this project is to identify the underlying mechanisms which finally contribute to the TH induced browning of white adipose tissue. This will be tested in three following subprojects addressing specific aims: (1) The discrimination of central and cellular effects of TH on WAT browning; (II) The characterization of the metabolic activity of the brown adipocytes in hyperthyroid WAT using PET/MRI, (III) Definition of the role of TH on alternatively activated macrophage induced thermogenesis. Perspectively, the stimulation of white adipose tissue browning via the action of TH might be translated into an effective therapy to raise energy expenditure.