Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure
Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure
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DOI：
10.2337/db13-0808
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发表时间：
2014-01-01
期刊：
影响因子：
7.7
通讯作者：
Yoneda, Yukio
中科院分区：
文献类型：
--
作者：
Hinoi, Eiichi;Nakamura, Yukari;Yoneda, Yukio
虽然生长分化因子-5（GDF 5）与哺乳动物的骨骼发育和关节形态发生有关，但对其在脂肪形成和能量稳态中的功能知之甚少。在这里，我们显示了GDF 5在调节小鼠全身能量消耗的棕色脂肪形成中的关键作用。GDF 5表达在先天性和获得性肥胖小鼠的棕色脂肪组织中优先上调。GDF 5在脂肪组织中的转基因过表达导致瘦表型，并通过增加全身能量消耗降低对饮食诱导的肥胖的易感性。GDF 5的过表达促进了腹股沟皮下白色脂肪组织中棕色脂肪样细胞（称为brite或beige细胞）的发育，同时沿着解偶联蛋白-1的表达。在携带显性阴性GDF 5的突变小鼠中，在致肥胖条件下观察到能量消耗和产热的显著损害。重组GDF 5促进棕色脂肪形成，通过母亲对decapentaplegic同源物（Smad）和过氧化物酶体增殖物激活受体-共激活因子-1（PGC-1）的途径后，激活骨形态发生蛋白受体（BMPR）。这些结果表明，棕色脂肪的形成和能量平衡都受到GDF 5/BMPR/Smad/PGC-1信号通路的正调控。调节这些通路可能是肥胖和2型糖尿病的有效治疗策略。
Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet-induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1 signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes.