Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
J Cell Physiol. 2021 Sep;236(9):6630-6642. doi: 10.1002/jcp.30307. Epub 2021 Feb 21.
Obesity is a major contributing factor to the pathogenesis of Type 2 diabetes. Multiple human genetics studies suggest that high activity of the low molecular weight protein tyrosine phosphatase (LMPTP) promotes metabolic syndrome in obesity. We reported that LMPTP is a critical promoter of insulin resistance in obesity by regulating liver insulin receptor signaling and that inhibition of LMPTP reverses obesity-associated diabetes in mice. Since LMPTP is expressed in adipose tissue but little is known about its function, here we examined the role of LMPTP in adipocyte biology. Using conditional knockout mice, we found that selective deletion of LMPTP in adipocytes impaired obesity-induced subcutaneous adipocyte hypertrophy. We assessed the role of LMPTP in adipogenesis in vitro, and found that LMPTP deletion or knockdown substantially impaired differentiation of primary preadipocytes and 3T3-L1 cells into adipocytes, respectively. Inhibition of LMPTP in 3T3-L1 preadipocytes also reduced adipogenesis and expression of proadipogenic transcription factors peroxisome proliferator activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha. Inhibition of LMPTP increased basal phosphorylation of platelet-derived growth factor receptor alpha (PDGFRα) on activation motif residue Y849 in 3T3-L1, resulting in increased activation of the mitogen-associated protein kinases p38 and c-Jun N-terminal kinase and increased PPARγ phosphorylation on inhibitory residue S82. Analysis of the metabolome of differentiating 3T3-L1 cells suggested that LMPTP inhibition decreased cell glucose utilization while enhancing mitochondrial respiration and nucleotide synthesis. In summary, we report a novel role for LMPTP as a key driver of adipocyte differentiation via control of PDGFRα signaling.
肥胖是 2 型糖尿病发病机制的一个主要促成因素。多项人类遗传学研究表明，低分子量蛋白酪氨酸磷酸酶（LMPTP）的高活性促进肥胖中的代谢综合征。我们报道 LMPTP 通过调节肝脏胰岛素受体信号是肥胖中胰岛素抵抗的关键促进因子，并且抑制 LMPTP 可逆转肥胖相关的小鼠糖尿病。由于 LMPTP 在脂肪组织中表达，但对其功能知之甚少，因此我们在此研究了 LMPTP 在脂肪细胞生物学中的作用。使用条件性敲除小鼠，我们发现脂肪细胞中 LMPTP 的选择性缺失会损害肥胖引起的皮下脂肪细胞肥大。我们评估了 LMPTP 在脂肪生成中的作用，体外发现 LMPTP 的缺失或敲低分别严重损害了原代前脂肪细胞和 3T3-L1 细胞向脂肪细胞的分化。在 3T3-L1 前脂肪细胞中抑制 LMPTP 也减少了脂肪生成和前脂肪生成转录因子过氧化物酶体增殖物激活受体γ（PPARγ）和 CCAAT/增强子结合蛋白α的表达。在 3T3-L1 前脂肪细胞中抑制 LMPTP 增加了血小板衍生生长因子受体α（PDGFRα）在激活基序残基 Y849 上的基础磷酸化，导致有丝分裂原相关蛋白激酶 p38 和 c-Jun N-末端激酶的激活增加，以及 PPARγ 在抑制性残基 S82 上的磷酸化增加。分化的 3T3-L1 细胞代谢组学分析表明，LMPTP 抑制降低了细胞葡萄糖利用，同时增强了线粒体呼吸和核苷酸合成。总之，我们报告了 LMPTP 作为通过控制 PDGFRα 信号控制脂肪细胞分化的关键驱动因子的新作用。
