Center for Cardiovascular Research, Institute of Pharmacology Charité-Universitätsmedizin Berlin, Germany.
Cardiovasc Diabetol. 2010 Oct 18;9:64. doi: 10.1186/1475-2840-9-64.
Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice.
In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD) for 10-weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle.
Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT-inflammation, ligand-activated PPARgamma improved diet-induced IR and GI.
Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma´s action.
脂肪组织（AT）的炎症最近被认为是肥胖介导的胰岛素抵抗的第一步。我们之前已经表明，喂食高脂肪饮食（HFD）的小鼠会发展出全身胰岛素抵抗（IR）和葡萄糖不耐受（GI），同时伴有 CD4 阳性 T 淋巴细胞浸润内脏脂肪组织。这些 T 淋巴细胞在脂肪组织中富集时，会参与脂肪组织炎症的发展以及随后促炎巨噬细胞的募集。这项工作的目的是阐明胰岛素增敏剂 PPARγ 在 IR 发展过程中对 T 淋巴细胞浸润的作用，并比较罗格列酮和替米沙坦在饮食诱导肥胖模型（DIO 模型）中对 PPARγ 介导的抗炎作用。
为了研究全身胰岛素抵抗和葡萄糖不耐受早期发展的分子机制，雄性 C57BL/6J 小鼠同时喂食高脂肪饮食（HFD）10 周，并进行罗格列酮、替米沙坦或载体的药物干预。
罗格列酮和替米沙坦均能通过定量分析 T 细胞标志物 CD3γ和趋化因子 SDF1α来减少 T 淋巴细胞浸润脂肪组织。随后，两种 PPARγ 激动剂均能减少巨噬细胞浸润脂肪组织，通过降低 MCP1 和 F4/80 的表达来衡量。与脂肪组织炎症的减少平行，配体激活的 PPARγ 改善了饮食诱导的 IR 和 GI。
本研究表明，PPARγ 介导的脂肪组织抗炎作用与全身葡萄糖代谢的改善密切相关，将 T 淋巴细胞鉴定为 PPARγ 作用的一种细胞介导物。
