Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin.
Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin.
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作者：
Gao S;McMillan RP;Jacas J;Zhu Q;Li X;Kumar GK;Casals N;Hegardt FG;Robbins PD;Lopaschuk GD;Hulver MW;Butler AA
体液因子对底物氧化的严格控制对于维持代谢稳态是必不可少的。在进食和禁食周期中，碳水化合物和脂肪酸是氧化代谢的两种主要底物。在这里，我们报告了一个新的作用肽激素肾上腺素调节底物氧化的喜好。Adropin的血浆水平随着进食而增加，并且在禁食时降低。Adropin敲除小鼠和转基因小鼠的全身底物偏好和骨骼肌底物氧化的比较表明Adropin促进碳水化合物氧化超过脂肪氧化。在肌肉中，Adropin激活丙酮酸脱氢酶（PDH），这是葡萄糖氧化的速率限制，并抑制肉毒碱棕榈酰转移酶-1B（CPT-1B），脂肪酸氧化的关键酶。Adropin下调抑制PDH的PDH激酶-4（PDK 4），从而增加PDH活性。Adropin作用的分子机制涉及转录辅激活因子PGC-1α的乙酰化（提示抑制），下调Cpt 1b和Pdk 4的表达。Adropin增加PGC-1α乙酰化可能通过抑制Sirtuin-1（SIRT 1）（一种PGC-1α脱乙酰酶）介导。SIRT 1和PGC-1α活性的改变似乎介导了Adropin在肌肉中的代谢作用。在用合成阿霉素处理的禁食小鼠中观察到类似的结果。总之，这些结果表明在各种营养状态下，Adropin在调节肌肉底物偏好方面的作用。
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.
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影响因子：
29
作者：
Kumar KG;Trevaskis JL;Lam DD;Sutton GM;Koza RA;Chouljenko VN;Kousoulas KG;Rogers PM;Kesterson RA;Thearle M;Ferrante AW Jr;Mynatt RL;Burris TP;Dong JZ;Halem HA;Culler MD;Heisler LK;Stephens JM;Butler AA
通讯作者：
Butler AA
影响因子：
5.5
作者：
Dawson, KD;Baker, DJ;Gibala, MJ
通讯作者：
Gibala, MJ
影响因子：
7.7
作者：
Keung W;Ussher JR;Jaswal JS;Raubenheimer M;Lam VH;Wagg CS;Lopaschuk GD
通讯作者：
Lopaschuk GD
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
4.3
作者：
Ford, Jack;Ahmed, Shafiq;Milner, Jo
通讯作者：
Milner, Jo