Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function.
Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function.
复制标题
DOI：
10.1016/j.cmet.2016.06.006
复制
发表时间：
2016-07-12
期刊：
影响因子：
29
通讯作者：
Steinberg GR
中科院分区：
文献类型：
--
作者：
Mottillo EP;Desjardins EM;Crane JD;Smith BK;Green AE;Ducommun S;Henriksen TI;Rebalka IA;Razi A;Sakamoto K;Scheele C;Kemp BE;Hawke TJ;Ortega J;Granneman JG;Steinberg GR
棕色 (BAT) 和白色 (WAT) 脂肪组织在维持全身能量稳态方面发挥着不同的作用，它们的功能障碍可能导致非酒精性脂肪肝 (NAFLD) 和 2 型糖尿病。 AMP 激活蛋白激酶 (AMPK) 是一种细胞能量传感器，但其在调节 BAT 和 WAT 代谢中的作用尚不清楚。我们构建了脂肪细胞中两个 AMPK β 亚基缺失的诱导模型 (iβ1β2AKO)，并发现 iβ1β2AKO 小鼠不耐受寒冷，并且对 BAT 的 β 肾上腺素激活和 WAT 的米色化具有抵抗力。 iβ1β2AKO 小鼠的 BAT 线粒体结构、功能和线粒体自噬标记物受损。为了应对高脂肪饮食，iβ1β2AKO 小鼠更快地出现肝脏脂肪变性以及葡萄糖和胰岛素不耐受。因此，脂肪细胞中的 AMPK 对于维持线粒体完整性、响应药物和热应激以及防止营养过剩引起的 NAFLD 和胰岛素抵抗至关重要。莫蒂洛等人。发现脂肪细胞中特别缺乏 AMPK 的小鼠不耐寒冷，并且对棕色和米色脂肪组织的 β 肾上腺素刺激具有抵抗力。这些缺陷与脂肪分解无关，是由线粒体自噬受损引起的，从而导致 BAT 线粒体缺陷、非酒精性脂肪肝和胰岛素抵抗。
Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance. Mottillo et al. find mice lacking AMPK specifically in adipocytes are intolerant to cold and resistant to β-adrenergic stimulation of brown and beige adipose tissues. These defects, independent of lipolysis, are caused by impaired mitophagy, which results in defective BAT mitochondria, non-alcoholic fatty liver disease, and insulin resistance.