Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor γ and C/EBPα.
Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor γ and C/EBPα.
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作者：
Yogosawa S;Mizutani S;Ogawa Y;Izumi T
我们之前在小鼠 2 号染色体上发现了肥胖、非胰岛素依赖型糖尿病 5 (Nidd5) 的数量性状基因座。在当前的研究中，我们发现 Nidd5 的实际遗传改变是编码激活素受体样激酶 7 (ALK7) 的 Acvr1c 基因的无义突变，ALK7 是 I 型转化生长因子-β 受体之一，导致激酶结构域 COOH 末端缺失。我们进一步表明，ALK7 功能障碍会导致脂肪细胞中的脂肪分解增加，并导致脂肪积累减少。相反，ALK7 激活通过抑制脂肪酶的表达来抑制脂肪分解。 ALK7 和激活的 Smad 通过下调过氧化物酶体增殖物激活受体 γ (PPARγ) 和 CCAAT/增强子结合蛋白 (C/EBP) α 来抑制这些脂肪酶。虽然 PPARγ 和 C/EBPα 在脂肪细胞分化过程中充当脂肪形成转录因子，但它们在分化的脂肪细胞中总体上具有脂解作用，并且在肥胖中被 ALK7 下调以积累脂肪。在肥胖状态下，ALK7 缺陷可通过优先增加小鼠的脂肪燃烧来改善葡萄糖耐量和胰岛素敏感性。这些发现揭示了分化脂肪细胞中 PPARγ 和 C/EBPα 的净脂肪分解功能，并指出肥胖中激活的 ALK7 信号通路是医疗干预的潜在目标。
We previously identified a quantitative trait locus for adiposity, non-insulin-dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator–activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP) α. Although PPARγ and C/EBPα act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARγ and C/EBPα in differentiated adipocytes and point to the ALK7-signaling pathway that is activated in obesity as a potential target of medical intervention.
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DOI：
10.1016/j.bbrc.2009.03.014
发表时间：
2009-05-01
影响因子：
3.1
作者：
Carlsson, Lena M. S.;Jacobson, Peter;Walley, Andrew;Froguel, Philippe;Sjostrom, Lars;Svensson, Per-Arne;Sjoholm, Kajsa
通讯作者：
Sjoholm, Kajsa
DOI：
10.1073/pnas.90.20.9606
发表时间：
1993-10-15
影响因子：
11.1
作者：
LIN, FT;MACDOUGALD, OA;LANE, MD
通讯作者：
LANE, MD
影响因子：
7.7
作者：
Langin, D;Dicker, A;Arner, P
通讯作者：
Arner, P
影响因子：
15.9
作者：
Okuno, A;Tamemoto, H;Kadowaki, T
通讯作者：
Kadowaki, T
影响因子：
0.7
作者：
Kogame, Masahiro;Matsuo, Shinji;Sugino, Hiromu
通讯作者：
Sugino, Hiromu