Gao Su, McMillan Ryan P, Jacas Jordi, Zhu Qingzhang, Li Xuesen, Kumar Ganesh K, Casals Núria, Hegardt Fausto G, Robbins Paul D, Lopaschuk Gary D, Hulver Matthew W, Butler Andrew A
Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL.
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA.
Diabetes. 2014 Oct;63(10):3242-52. doi: 10.2337/db14-0388. Epub 2014 May 21.
Rigorous control of substrate oxidation by humoral factors is essential for maintaining metabolic homeostasis. During feeding and fasting cycles, carbohydrates and fatty acids are the two primary substrates in oxidative metabolism. Here, we report a novel role for the peptide hormone adropin in regulating substrate oxidation preferences. Plasma levels of adropin increase with feeding and decrease upon fasting. A comparison of whole-body substrate preference and skeletal muscle substrate oxidation in adropin knockout and transgenic mice suggests adropin promotes carbohydrate oxidation over fat oxidation. In muscle, adropin activates pyruvate dehydrogenase (PDH), which is rate limiting for glucose oxidation and suppresses carnitine palmitoyltransferase-1B (CPT-1B), a key enzyme in fatty acid oxidation. Adropin downregulates PDH kinase-4 (PDK4) that inhibits PDH, thereby increasing PDH activity. The molecular mechanisms of adropin's effects involve acetylation (suggesting inhibition) of the transcriptional coactivator PGC-1α, downregulating expression of Cpt1b and Pdk4. Increased PGC-1α acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC-1α deacetylase. Altered SIRT1 and PGC-1α activity appear to mediate aspects of adropin's metabolic actions in muscle. Similar outcomes were observed in fasted mice treated with synthetic adropin. Together, these results suggest a role for adropin in regulating muscle substrate preference under various nutritional states.
通过体液因子严格控制底物氧化对于维持代谢稳态至关重要。在进食和禁食周期中，碳水化合物和脂肪酸是氧化代谢中的两种主要底物。在此，我们报告了肽激素内脂素在调节底物氧化偏好方面的新作用。内脂素的血浆水平随进食而升高，禁食时则降低。对敲除内脂素和转基因小鼠的全身底物偏好和骨骼肌底物氧化进行比较表明，内脂素促进碳水化合物氧化而非脂肪氧化。在肌肉中，内脂素激活丙酮酸脱氢酶（PDH），其是葡萄糖氧化的限速酶，并抑制肉碱棕榈酰转移酶-1B（CPT-1B），这是脂肪酸氧化中的关键酶。内脂素下调抑制PDH的PDH激酶-4（PDK4），从而增加PDH活性。内脂素作用的分子机制涉及转录共激活因子PGC-1α的乙酰化（提示抑制作用），下调Cpt1b和Pdk4的表达。内脂素增加PGC-1α的乙酰化可能是通过抑制Sirtuin-1（SIRT1），一种PGC-1α脱乙酰酶来介导的。SIRT1和PGC-1α活性的改变似乎介导了内脂素在肌肉中的代谢作用的各个方面。在用合成内脂素处理的禁食小鼠中也观察到了类似的结果。总之，这些结果表明内脂素在调节各种营养状态下的肌肉底物偏好中发挥作用。
