Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Cell Physiol. 2010 Nov;299(5):C1162-70. doi: 10.1152/ajpcell.00188.2010. Epub 2010 Aug 25.
Fatty acid reesterification in adipose tissue is dependent on the generation of glycerol 3-phosphate, and, at least in rodent adipose tissue, this appears to occur primarily through glyceroneogenesis. A key enzyme in this process is pyruvate dehydrogenase kinase 4 (PDK4). PDK4 is induced in white adipose tissue by thiazolidinediones (TZDs) and the inhibition or knockdown of PDK4 inhibits TZD-induced increases in glyceroneogenesis. Since TZDs have many unwanted side effects, we were interested in identifying alternative mechanisms that could regulate PDK4 mRNA expression in white adipose tissue. In this regard we hypothesized that exercise, fasting, and epinephrine would increase PDK4 mRNA levels in rat epididymal adipose tissue. We further postulated that the p38 mitogen-activated protein kinase (MAPK) and 5'-AMP-activated protein kinase (AMPK) signaling pathways would control PDK4 mRNA expression in cultured adipose tissue. Exercise, fasting, and in or ex vivo epinephrine treatment increased PDK4 mRNA levels. These perturbations did not increase the expression of PDK1, -2, or -3. Pyruvate dehydrogenase phosphorylation was increased after an overnight fast and 4 h after the cessation of exercise. In cultured adipose tissue, epinephrine increased p38 and AMPK signaling; however, the direct activation of AMPK by AICAR or metformin led to reductions in PDK4 mRNA levels. The p38 inhibitor SB202190 reduced epinephrine-mediated increases in p38 MAPK activation without altering hormone-sensitive lipase or AMPK phosphorylation or attenuating epinephrine-induced increases in lipolysis. Reductions in p38 MAPK signaling were associated with decreases in PDK4 mRNA expression. The inhibition of peroxisome proliferator-activated receptor-γ (PPARγ) also attenuated the induction of PDK4. Our results are the very first to demonstrate an epinephrine-mediated regulation of PDK4 mRNA levels in white adipose tissue and suggest that p38 MAPK and PPARγ could be involved in this pathway.
脂肪组织中的脂肪酸再酯化依赖于甘油 3-磷酸的产生，至少在啮齿动物脂肪组织中，这似乎主要通过甘油酮生成发生。这个过程中的关键酶是丙酮酸脱氢酶激酶 4（PDK4）。噻唑烷二酮（TZDs）诱导白色脂肪组织中 PDK4 的产生，抑制或敲低 PDK4 可抑制 TZD 诱导的甘油酮生成增加。由于 TZDs 有许多不良副作用，我们有兴趣确定其他可以调节白色脂肪组织中 PDK4 mRNA 表达的机制。在这方面，我们假设运动、禁食和肾上腺素会增加大鼠附睾脂肪组织中 PDK4 mRNA 的水平。我们进一步假设 p38 丝裂原活化蛋白激酶（MAPK）和 5'-AMP 激活蛋白激酶（AMPK）信号通路可以控制培养脂肪组织中 PDK4 mRNA 的表达。运动、禁食和体内或体外肾上腺素处理均增加 PDK4 mRNA 水平。这些干扰不会增加 PDK1、-2 或 -3 的表达。 overnight fast 和运动停止后 4 h，丙酮酸脱氢酶磷酸化增加。在培养的脂肪组织中，肾上腺素增加了 p38 和 AMPK 信号；然而，AICAR 或二甲双胍直接激活 AMPK 导致 PDK4 mRNA 水平降低。p38 抑制剂 SB202190 降低了肾上腺素介导的 p38 MAPK 激活增加，但不改变激素敏感脂肪酶或 AMPK 磷酸化，也不减弱肾上腺素诱导的脂肪分解增加。p38 MAPK 信号的减少与 PDK4 mRNA 表达的减少有关。过氧化物酶体增殖物激活受体-γ（PPARγ）的抑制也减弱了 PDK4 的诱导。我们的研究结果首次证明了肾上腺素介导的白色脂肪组织中 PDK4 mRNA 水平的调节，并表明 p38 MAPK 和 PPARγ 可能参与这一途径。
