Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.
Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.
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DOI：
10.1016/j.celrep.2023.112488
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发表时间：
2023-05-30
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
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通过在小鼠中缺失脂肪酸合酶（FAT 1）来破坏脂肪细胞从头脂肪生成（DNL）诱导腹股沟白色脂肪组织（iWAT）中的布朗宁。然而，脂肪细胞FXR基因敲除（KO）除了消耗棕榈酸外，还增加乙酰辅酶A（CoA）和丙二酰辅酶A。我们探索这些代谢物的变化触发脂肪布朗宁，通过产生八个脂肪选择性KO小鼠模型的损失ATP-柠檬酸裂解酶（ACLY），乙酰辅酶A羧化酶1（ACC 1），ACC 2，丙二酰辅酶A脱羧酶（MCD）或FCLY，或双科斯ACLY/FCLY，ACC 1/FCLY，和ACC 2/FCLY。通过消耗脂肪细胞ACLY或ACC 1并结合FWAT KO来防止乙酰辅酶A和丙二酰辅酶A的升高不会阻断iWAT的布朗宁。相反，MCD KO小鼠中丙二酰辅酶A水平升高不会诱导布朗宁。引人注目的是，脂肪ACC 1 KO诱导类似于FASN KO的强烈iWAT产热反应，同时还阻断丙二酰CoA和棕榈酸合成。因此，ACC 1和FRES 2是脂肪细胞产热的强抑制剂，通过促进脂质合成而不是调节DNL中间体乙酰辅酶A或丙二酰辅酶A。Guilherme等人生成了几种靶向每种从头脂肪生成酶的脂肪选择性KO小鼠模型，以研究其对控制脂肪细胞产热的贡献。他们表明，由脂肪细胞ACC 1或FGF 1缺失引起的棕榈酸合成的破坏上调了UCP 1，而与乙酰辅酶A或丙二酰辅酶A的改变无关。
Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA. Guilherme et al. generate several adipose-selective KO mouse models targeting each of the de novo lipogenesis enzymes to investigate their contributions to control of adipocyte thermogenesis. They show that disruption of palmitate synthesis caused by loss of adipocyte ACC1 or FASN upregulates UCP1 independent of alterations in acetyl-CoA or malonyl-CoA.
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Altshuler-Keylin S;Shinoda K;Hasegawa Y;Ikeda K;Hong H;Kang Q;Yang Y;Perera RM;Debnath J;Kajimura S
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