肝脏PPARA对白色脂肪米色化的调控机制

Our recent study indicated that Ppara-null in mice promoted white adipose beiging, while its regulative mechanism is yet unknown. Our further study reveals that: 1) Ppara-null increased serum glucagon, 2) glucagon can stimulate oxygen consumption in white adipocytes in a dose-dependent way, 3）Ppara liver-specific knockout in mice promoted white adipose beiging and increased serum glucagon, and 4) Ppara-null and Ppara liver-specific knockout in mice lower gluconeogenesis. Therefore, we propose that “PPARA deficiency might depress gluconeogenesis, which then upregulates serum glucagon, and subsequently promotes white adipose beiging”. To confirm the potential signaling mechanism for PPARA deficiency-induced white adipose beiging, several experimental models will be created based on Ppara-null mouse, Ppara liver-specific knockout mouse, 3T3-L1 cell line, and primary adipocytes from mice. Some analysis methods based on immunohistochemistry, cell biology and molecular biology will be used. This study will hold great promise for revealing novel roles and molecular mechanisms for PPARA in regulating white adipose beiging, and may provide a novel therapy target for the prevention and intervention of obesity-related metabolic syndrome in human.

我们最近的研究结果表明：PPARA敲除能导致白色脂肪米色化，但其具体调控机制仍未明了。我们进一步研究发现: 1) PPARA敲除会上调血清胰高血糖素水平，2)胰高血糖素能剂量依赖性地刺激脂肪细胞的耗氧量上升，3)肝脏特异性PPARA敲除也能导致白色脂肪米色化和上调血清胰高血糖素水平, 4)PPARA敲除和肝脏特异性PPARA敲除均导致糖异生功能受损。因此，我们提出“PPARA缺失导致糖异生途径受阻，进而上调血清胰高血糖水平，从而导致白色脂肪米色化”的研究假说。根据研究假说，本项目将以PPARA敲除小鼠、肝脏特异性PPARA敲除小鼠、3T3-L1前脂肪细胞、以及急性分离脂肪细胞为模型，利用组织化学、细胞生物学和分子生物学等研究手段，验证PPARA缺失导致白色脂肪米色化的潜在信号机制，为预防和干预人体肥胖相关代谢综合征筛选可能的新靶点。

背景和目的：近年来，随着肥胖的流行率不断上升，肥胖和相关代谢综合征对健康的挑战越来越大，考虑到激活棕色脂肪或者诱导白色脂肪米色化在抑制肥胖和相关代谢综合征的发生发展过程中的重要作用，结合我们的前期数据表明PPARA参与了肥胖和代谢综合征的调控，本项目探索了PPARA对白色脂肪米色化和相关代谢综合征的调控机制。..结果：小鼠PPARA敲除会上调血清胰高血糖素水平，并导致胰高血糖素抵抗和糖异生受损，进而代偿性地导致白色脂肪米色化和脂肪水解加剧。胰高血糖素抵抗和糖异生受损破坏了机体糖代谢的稳态，使白色脂肪米色化失去减肥效应，并导致肝脏脂肪的异常积累和肝纤维化的发生。同时激活PPARA和胰高血糖素受体能显著改善高脂饮食诱导的脂肪肝和肝纤维化。..科学意义：这些发现表明，PPARA是干预代谢综合征相关肝纤维化的潜在靶点，共同激活PPARA和胰高血糖素受体对改善代谢综合征（尤其是干预肝纤维化）具有重要意义。