Adipose tissue lipolysis is regulated by PAQR11 via altering protein stability of phosphodiesterase 4D.
Adipose tissue lipolysis is regulated by PAQR11 via altering protein stability of phosphodiesterase 4D.
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PAQR11 通过改变磷酸二酯酶 4D 的蛋白质稳定性来调节脂肪组织脂肪分解
DOI：
10.1016/j.molmet.2021.101182
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发表时间：
2021-05
影响因子：
8.1
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Huang M;Lin Y;Wang L;You X;Wang S;Zhao J;Bai M;Li Z;Chen Y
脂肪组织中脂肪的储存和动员在能量代谢中起着核心作用，并与肥胖的发展直接相关。饥饿时，脂肪通过脂肪分解从脂肪组织中动员出来，这一过程将甘油三酯水解成游离脂肪酸，作为骨骼肌和其他组织的能量来源。然而，饥饿是如何激活脂肪分解的还不完全清楚。在这项研究中，我们证明了PAQR11，孕酮和AdipoQ受体家族的成员，调节饥饿介导的脂解。Paqr11缺失的小鼠对高脂饮食诱导的肥胖具有抵抗力。Paqr11缺失促进白色脂肪组织的脂肪分解，其特征是激素敏感脂肪酶(HSL)和Perilipin 1(PLIN1)的磷酸化增加，以及血清甘油和游离脂肪酸水平上升。白色脂肪组织中PKA活性和cAMP水平也因Paqr11缺失而增加，同时伴随着磷酸二酯酶4D(PDE4D)的加速蛋白降解。在机制上，PAQR11减少了PDE4D与Skp1-CUL1-FBXO2 E3连接酶复合体的相互作用，从而调节了PDE4D的多泛素化/降解。禁食降低了Paqr11基因的表达，白色脂肪组织中饥饿诱导的脂解通过Paqr11缺失而增强，而胰岛素介导的脂解抑制不受影响。综上所述，这些结果表明，PAQR11调节脂肪组织的脂肪分解，并影响高脂饮食诱导的肥胖。Paqr11缺失可促进附睾白脂肪组织的脂解作用。PAQR11通过改变PDE4D的蛋白降解来调节cAMP水平。PAQR11影响PDE4D与Skp1-CUL1-FBXO2 E3连接酶复合体的相互作用。PAQR11调节饥饿诱导的脂肪组织的脂解作用。
Fat storage and mobilization in adipose tissue play a central role in energy metabolism and are directly linked to the development of obesity. Upon starvation, fat is mobilized from adipose tissue by lipolysis, a process by which triglycerides are hydrolyzed to free fatty acids to be used as an energy source in skeletal muscles and other tissues. However, how lipolysis is activated by starvation is not fully known. In this study, we demonstrate that PAQR11, a member of the progesterone and AdipoQ receptor family, regulates starvation-mediated lipolysis. Paqr11-deleted mice are resistant to high-fat diet-induced obesity. Paqr11 deletion promotes lipolysis in white adipose tissue, characterized by increased phosphorylations of hormone-sensitive lipase (HSL) and perilipin 1 (PLIN1) and elevated serum levels of glycerol and free fatty acids. PKA activity and cAMP levels in white adipose tissue are also increased by Paqr11 deletion, accompanied by accelerated protein degradation of phosphodiesterase 4D (PDE4D). Mechanistically, PAQR11 decreases the interaction of PDE4D with SKP1-CUL1-FBXO2 E3 ligase complex, thus modulating the polyubiquitination/degradation of PDE4D. Fasting decreases the expression of the Paqr11 gene, and starvation-induced lipolysis in white adipose tissue is enhanced by Paqr11 deletion, while insulin-mediated suppression of lipolysis is not affected. Collectively, these results reveal that PAQR11 regulates lipolysis of adipose tissue and affects high-fat diet-induced obesity. Paqr11 deletion promotes lipolysis in epididymal white adipose tissue. PAQR11 modulates cAMP level by altering protein degradation of PDE4D. PAQR11 affects the interaction of PDE4D with SKP1-CUL1-FBXO2 E3 ligase complex. PAQR11 regulates starvation-induced lipolysis in adipose tissue.
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