Intraperitoneal Injection of Clodronate Liposomes Eliminates Visceral Adipose Macrophages and Blocks High-fat Diet-induced Weight Gain and Development of Insulin Resistance

被引:78
作者
Bu, Le [1 ,2 ]
Gao, Mingming [2 ]
Qu, Shen [1 ]
Liu, Dexi [2 ]
机构
[1] Tongji Univ, Peoples Hosp Shanghai 10, Shanghai 200092, Peoples R China
[2] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA
基金
美国国家科学基金会;
关键词
high-fat diet-induced obesity; inflammation; insulin resistance; liposomes; visceral adipose tissue macrophage; NECROSIS-FACTOR-ALPHA; KUPFFER CELLS; OBESITY; TISSUE; ANGIOGENESIS; INFLAMMATION; INFILTRATION; EXPRESSION;
D O I
10.1208/s12248-013-9501-7
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Macrophage infiltration in adipose tissue is strongly correlated with obesity. The exact role of macrophage in the development of obesity, however, has not been fully understood. In this study, using intraperitoneal injection of clodronate liposomes, we tissue-specifically depleted visceral adipose tissue macrophages (VATMs) and explored their roles in initiation and progression of obesity. Two sets of experiments were conducted, using mice on a high-fat diet as the animal model. Mice were injected with clodronate liposomes at the beginning of high-fat diet feeding to investigate the role of VATMs in the initiation of obesity. Treatment starting on week 5 was designed to explore the function of VATMs in the progression of weight gain. The results show that intraperitoneal injection of clodronate liposomes effectively depleted VATMs, which blocked high-fat diet-induced weight gain, fat accumulation, insulin resistance, and hepatic steatosis. Similarly, clodronate liposomes suppressed progression of weight gain in mice after being fed with a high-fat diet for 4 weeks and improved insulin sensitivity. Gene expression analysis showed that depletion of VATMs was associated with downregulation of the expression of genes involved in lipogenesis and gluconeogenesis including acc1, fas, scd1, and pepck, decreased expression of genes involved in chronic inflammation including mcp1 and tnf alpha, and suppressed expression of macrophage specific marker genes of f4/80 and cd11c in adipose tissue. Depletion of VATMs was associated with prevention of the formation of crown-like structures in white adipose tissue and the maintenance of a low level of blood TNF-alpha. Collectively, these data demonstrate that VATMs appeared to play a crucial role in the development of obesity and obesity-associated diseases and suggest that adipose tissue macrophages could be regarded as a potential target for drug development in prevention and therapy of obesity and obesity-associated complications.
引用
收藏
页码:1001 / 1011
页数:11
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