Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ
Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ
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DOI：
10.1073/pnas.1314863110
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发表时间：
2013-11-12
影响因子：
11.1
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Wang, Fenfen;Mullican, Shannon E.;Lazar, Mitchell A.
脂肪组织是重要的代谢器官，其功能障碍与肥胖、糖尿病和心血管疾病的发生有关。核受体过氧化物酶体增殖物激活受体γ（PPAR γ）被认为是脂肪细胞分化和功能的主要调节因子。尽管其在脂肪形成中的细胞自主作用已在细胞培养中得到明确证明，但之前对小鼠PPAR γ基因的脂肪特异性敲除并未在体内表现出显着的表型。在这里，使用Adipoq-Cre小鼠驱动脂肪特异性重组，我们报告了一种独特的脂肪特异性PPAR γ敲除（PPAR。FKO）小鼠模型，在3月龄时几乎没有可见的棕色和白色脂肪组织。因此，PPAR γ FKO小鼠具有巨大的胰岛，大量脂肪肝，血糖和血清胰岛素水平显著升高，伴有极端的胰岛素抵抗。PPARgamma FKO小鼠还表现出与真皮脂肪缺失相关的被毛形成延迟、乳腺发育中断伴乳腺脂肪垫丢失以及高骨量伴骨髓脂肪丢失，表明脂肪PPARgamma在这些组织中的关键作用。总之，我们的数据揭示了脂肪PPAR γ在脂肪形成、全身代谢稳态和含脂肪组织正常发育中的必要性。
Adipose tissue is an important metabolic organ, the dysfunction of which is associated with the development of obesity, diabetes mellitus, and cardiovascular disease. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is considered the master regulator of adipocyte differentiation and function. Although its cell-autonomous role in adipogenesis has been clearly demonstrated in cell culture, previous fat-specific knockouts of the murine PPAR gamma gene did not demonstrate a dramatic phenotype in vivo. Here, using Adipoq-Cre mice to drive adipose-specific recombination, we report a unique fat-specific PPAR gamma knockout (PPAR. FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo. As a consequence, PPAR gamma FKO mice had hugely enlarged pancreatic islets, massive fatty livers, and dramatically elevated levels of blood glucose and serum insulin accompanied by extreme insulin resistance. PPAR gamma FKO mice also exhibited delayed hair coat formation associated with absence of dermal fat, disrupted mammary gland development with loss of mammary fat pads, and high bone mass with loss of bone marrow fat, indicating the critical roles of adipose PPAR gamma in these tissues. Together, our data reveal the necessity of fat PPAR gamma in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues.