Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor
Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor
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DOI：
10.1210/en.2005-0003
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发表时间：
2005-08-01
期刊：
影响因子：
4.8
通讯作者：
Ogawa, Y
中科院分区：
文献类型：
--
作者：
Kouyama, R;Suganami, T;Ogawa, Y
鉴于血管紧张素II(AII)1型和2型受体(Agtr1和Agtr2)在脂肪组织中表达，AII可能直接作用于脂肪组织。然而，无论AII是否直接调节体内脂肪组织的生长和代谢，如果是，是否通过Agtr1介导仍然是争论的问题。为了了解Agtr1在体内脂肪组织生长和代谢中的功能作用，我们研究了缺乏Agtr1a的小鼠(Agtr1a(-/-)小鼠)在高脂饮食中的代谢表型。与野生型小鼠相比，Agtr1a(-/-)小鼠表现出减轻饮食诱导的体重增加和肥胖，以及胰岛素抵抗。他们还表现出伴随交感神经激活的能量消耗增加，表现为直肠温度和氧耗增加，棕色脂肪组织解偶联蛋白-1mRNA表达增加，尿儿茶酚胺排泄量增加。杂合Agtr1a缺陷小鼠(Agtr1a(+/+)小鼠)也表现出与Agtr1a(+/+)小鼠相似的代谢表型。使用来自Agtr1a(+/+)和Agtr1a(-/-)小鼠的小鼠胚胎成纤维细胞，我们发现不同的基因类型在分化为富含脂质的成熟脂肪细胞的能力方面没有显著差异。在原代培养的小鼠成熟脂肪细胞中，AII增加了某些脂肪细胞因子的mRNAs的表达，这一作用可被Agtr1的药物阻断所消除。这项研究表明，Agtr1a(-/-)小鼠通过增加能量消耗来减轻饮食诱导的体重增加和肥胖。这些数据还表明，AII不直接影响脂肪细胞的分化，但可以通过Agtr1调节脂肪细胞因子的产生。
Given that angiotensin II (AII) type 1 and 2 receptors (Agtr1 and Agtr2) are expressed in adipose tissue, AII may act directly on adipose tissue. However, regardless of whether AII directly modulates adipose tissue growth and metabolism in vivo and, if so, whether it is mediated via Agtr1 are still matters of debate. To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtr1a (Agtr1a(-/-) mice) during a high-fat diet. The Agtr1a(-/-) mice exhibited the attenuation of diet-induced body weight gain and adiposity, and insulin resistance relative to wild-type littermates (Agtr1a(+/+) mice). They also showed increased energy expenditure accompanied by sympathetic activation, as revealed by increased rectal temperature and oxygen consumption, increased expression of uncoupling protein-1 mRNA in brown adipose tissue, and increased urinary catecholamine excretion. The heterozygous Agtr1a-deficient mice (Agtr1a(+/+) mice) also exhibited metabolic phenotypes similar to those of Agtr1a(+/+) mice. Using mouse embryonic fibroblasts derived from Agtr1a(+/+) and Agtr1a(-/-) mice, we found no significant difference between genotypes in the ability to differentiate into lipid-laden mature adipocytes. In primary cultures of mouse mature adipocytes, AII increased the expression of mRNAs for some adipocytokines, which was abolished by pharmacological blockade of Agtr1. This study demonstrates that Agtr1a(-/-) mice exhibit attenuation of diet-induced weight gain and adiposity through increased energy expenditure. The data also suggest that AII does not affect directly adipocyte differentiation, but can modulate adipocytokine production via Agtr1.