Biozentrum, University of Basel, Basel, Switzerland.
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Am J Physiol Endocrinol Metab. 2023 Jun 1;324(6):E589-E598. doi: 10.1152/ajpendo.00338.2022. Epub 2023 May 11.
Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that plays an important role in energy homeostasis. Loss of adipose mTORC2 reduces lipogenic enzyme expression and de novo lipogenesis in adipose tissue. Adipose-specific mTORC2 knockout mice also display triglyceride accumulation in the liver. However, the mechanism and physiological role of hepatic triglyceride accumulation upon loss of adipose mTORC2 are unknown. Here, we show that loss of adipose mTORC2 increases the expression of de novo lipogenic enzymes in the liver, thereby causing accumulation of hepatic triglyceride and hypertriglyceridemia. Simultaneous inhibition of lipogenic enzymes in adipose tissue and liver by ablating mTORC2 in both tissues prevented accumulation of hepatic triglycerides and hypertriglyceridemia. However, loss of adipose and hepatic mTORC2 caused severe insulin resistance and glucose intolerance. Thus our findings suggest that increased hepatic lipogenesis is a compensatory mechanism to cope with loss of lipogenesis in adipose tissue, and further suggest that mTORC2 in adipose tissue and liver plays a crucial role in maintaining whole body energy homeostasis. Loss of adipose and hepatic mTORC2 causes diabetes.
哺乳动物雷帕霉素靶蛋白复合物 2（mTORC2）是一种蛋白激酶复合物，在能量稳态中发挥重要作用。脂肪组织中 mTORC2 的缺失会降低脂肪生成酶的表达和从头脂肪生成。脂肪组织特异性 mTORC2 敲除小鼠的肝脏也会出现甘油三酯积累。然而，脂肪组织 mTORC2 缺失导致肝脏甘油三酯积累的机制和生理作用尚不清楚。本文中，我们发现脂肪组织 mTORC2 的缺失会增加肝脏中从头脂肪生成酶的表达，从而导致肝脏甘油三酯的积累和高甘油三酯血症。通过同时抑制脂肪组织和肝脏中的脂肪生成酶，消除两种组织中的 mTORC2，可防止肝脏甘油三酯的积累和高甘油三酯血症。然而，脂肪组织和肝脏 mTORC2 的缺失会导致严重的胰岛素抵抗和葡萄糖不耐受。因此，我们的研究结果表明，肝脏脂肪生成的增加是一种代偿机制，以应对脂肪组织中脂肪生成的减少，进一步表明脂肪组织和肝脏中的 mTORC2 在维持全身能量稳态中起着关键作用。脂肪组织和肝脏 mTORC2 的缺失会导致糖尿病。
