Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance.
Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance.
复制标题
DOI：
10.1016/j.molmet.2021.101300
复制
发表时间：
2021-11
影响因子：
8.1
通讯作者：
Ozcan L
中科院分区：
文献类型：
--
作者：
Dai W;Choubey M;Patel S;Singer HA;Ozcan L
肥胖相关的脂肪组织功能障碍与胰岛素抵抗、2型糖尿病和心血管疾病的发展有关。钙稳态受损与脂肪组织代谢改变有关;然而，将钙信号传导中断与代谢调节联系起来的分子机制在很大程度上尚不清楚。在这里，我们研究了钙敏感酶，钙/钙调蛋白依赖性蛋白激酶II（CAMK 2），脂肪细胞功能，肥胖相关的胰岛素抵抗和葡萄糖耐受不良的贡献。为了确定脂肪细胞CAMK 2缺陷对代谢调节的影响，我们产生了条件性敲除小鼠模型，并在成熟脂肪细胞中急性缺失CAMK 2。我们进一步使用体外分化的脂肪细胞来剖析CAMK 2调节脂肪细胞功能的机制。肥胖脂肪组织中CAMK 2活性增加，成年小鼠中脂肪细胞CAMK 2的耗竭改善了葡萄糖耐受不良和胰岛素抵抗，而对体重没有影响。从机制上讲，我们发现CAMK 2的激活破坏了脂肪细胞胰岛素信号传导，降低了胰岛素受体的数量。此外，我们的研究结果表明，CAMK 2有助于脂肪细胞脂解，肿瘤坏死因子α（TNFα）诱导的炎症和胰岛素抵抗。这些结果确定了脂肪细胞CAMK 2活性，代谢调节和全身葡萄糖稳态之间的新联系。肥胖小鼠脂肪组织中CAMK 2活性增加。CAMK 2抑制或缺乏通过增加胰岛素受体水平来改善脂肪细胞胰岛素信号传导。脂肪细胞-CAMK 2缺乏可防止肥胖诱导的葡萄糖耐受不良和胰岛素抵抗CAMK 2调节脂肪细胞脂解和炎症。
Obesity-related adipose tissue dysfunction has been linked to the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Impaired calcium homeostasis is associated with altered adipose tissue metabolism; however, the molecular mechanisms that link disrupted calcium signaling to metabolic regulation are largely unknown. Here, we investigated the contribution of a calcium-sensing enzyme, calcium/calmodulin-dependent protein kinase II (CAMK2), to adipocyte function, obesity-associated insulin resistance, and glucose intolerance. To determine the impact of adipocyte CAMK2 deficiency on metabolic regulation, we generated a conditional knockout mouse model and acutely deleted CAMK2 in mature adipocytes. We further used in vitro differentiated adipocytes to dissect the mechanisms by which CAMK2 regulates adipocyte function. CAMK2 activity was increased in obese adipose tissue, and depletion of adipocyte CAMK2 in adult mice improved glucose intolerance and insulin resistance without an effect on body weight. Mechanistically, we found that activation of CAMK2 disrupted adipocyte insulin signaling and lowered the amount of insulin receptor. Further, our results revealed that CAMK2 contributed to adipocyte lipolysis, tumor necrosis factor alpha (TNFα)–induced inflammation, and insulin resistance. These results identify a new link between adipocyte CAMK2 activity, metabolic regulation, and whole-body glucose homeostasis. CAMK2 activity is increased in obese mice adipose tissue. CAMK2 inhibition or deficiency improves adipocyte insulin signaling via increasing insulin receptor levels. Adipocyte-CAMK2 deficiency protects against obesity-induced glucose intolerance and insulin resistance. CAMK2 regulates adipocyte lipolysis and inflammation.
登录
查看更多内容
影响因子：
12.8
作者：
Cho YM;Kim DH;Lee KH;Jeong SW;Kwon OJ
通讯作者：
Kwon OJ
影响因子：
7.2
作者：
Bhattacharyya, Moitrayee;Karandur, Deepti;Kuriyan, John
通讯作者：
Kuriyan, John
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
影响因子：
7.7
作者：
Chen, Jessy;Fleming, Thomas;Backs, Johannes
通讯作者：
Backs, Johannes
影响因子：
29
作者：
Eguchi J;Wang X;Yu S;Kershaw EE;Chiu PC;Dushay J;Estall JL;Klein U;Maratos-Flier E;Rosen ED
通讯作者：
Rosen ED