Dube Michael G, Torto Rita, Kalra Satya P
Department of Physiology and Functional Genomics, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610-0244, USA.
Peptides. 2008 Apr;29(4):593-8. doi: 10.1016/j.peptides.2008.01.001. Epub 2008 Jan 17.
Low-grade systemic inflammation, as indicated by increased circulating levels of inflammatory markers CRP and IL-6, is linked to increased risks for cardiovascular diseases (CVD) and diabetes mellitus in obese subjects. Whereas hyperleptinemia in obesity are associated with increased CRP and IL-6 release, the hypothalamic versus peripheral site of leptin action has not been ascertained. The effects of increased leptin supply selectively in the hypothalamus by gene therapy on pro-inflammatory CRP and IL-6 levels and on markers of diabetes in the circulation of ob/ob mice displaying either age-related or dietary obesity were assessed. A recombinant adeno-associated viral vector encoding either green-fluorescent protein (control) or leptin gene was injected intracerebroventricularly. Five weeks later, one-half of each of the vector groups was switched to high-fat diet consumption and the other half continued to consume regular low-fat chow diet. Body weight and visceral white adipose tissue were drastically reduced and hyperinsulinemia and hyperglycemia were abrogated by leptin gene therapy, independent of the dietary fat content. The elevated plasma CRP and IL-6 levels seen in obese ob/ob mice receiving the control vector, regardless of the fat content of the diet, were markedly suppressed by increased hypothalamic leptin in both groups. The results show for the first time that leptin deficiency elevates and reinstatement of leptin selectively in the hypothalamus suppresses the release of pro-inflammatory biomarkers, a response likely to alleviate CVD associated with obesity.
炎症标志物CRP和IL-6循环水平升高表明存在低度全身炎症，这与肥胖受试者患心血管疾病（CVD）和糖尿病的风险增加有关。虽然肥胖中的高瘦素血症与CRP和IL-6释放增加有关，但瘦素作用的下丘脑部位与外周部位尚未确定。评估了通过基因治疗在下丘脑中选择性增加瘦素供应对显示年龄相关性肥胖或饮食性肥胖的ob/ob小鼠循环中促炎CRP和IL-6水平以及糖尿病标志物的影响。将编码绿色荧光蛋白（对照）或瘦素基因的重组腺相关病毒载体脑室内注射。五周后，每个载体组的一半改为食用高脂饮食，另一半继续食用常规低脂食物。瘦素基因治疗可显著降低体重和内脏白色脂肪组织，消除高胰岛素血症和高血糖症，且与饮食脂肪含量无关。无论饮食脂肪含量如何，接受对照载体的肥胖ob/ob小鼠中升高的血浆CRP和IL-6水平在两组中均被下丘脑瘦素增加显著抑制。结果首次表明，瘦素缺乏会升高促炎生物标志物的释放，而下丘脑中瘦素的恢复则会抑制其释放，这种反应可能会减轻与肥胖相关的心血管疾病。
