Investigation of genes involved in anti-obesity and insulin sensitivity in the white adipose tissue

白色脂肪组织中抗肥胖和胰岛素敏感性相关基因的研究

• 批准号: 16590317
• 负责人: HIGAMI Yoshikazu
• 金额: $ 2.3万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590317/
• 关键词: calorie restriction; growth hormone; IGF-1; transgenic rats; insulin sensitivity; white adipose tissue; adipocytokine; DNA chip; SREBP-1; アディポネクチン

Caloric restriction (CR) is the simplest experimental manipulation known to extend lifespan and to retard a broad spectrum of age-associated pathophysiological changes in laboratory rodents. The exact underlying mechanisms are still unknown, but CR animals share many characteristics with long-living dwarf mice, including smaller body size, lower plasma insulin and IGF-1 levels, and higher insulin sensitivity. Recently, white adipose tissue (WAT) has been recognized as an endocrine organ, and its dysfunction influences insulin sensitivity, onset of type 2 diabetes, its complications, aging and longevity. To clarify the relationship between the effects of GH/IGF-1 suppression and CR, we have previously examined the survival and insulin sensitivity of male wild type (-/-) rats fed either ad libitum (AL) or subjected to 30% CR, and heterozygous transgenic dwarf rats (DF) bearing an anti-sense GH transgene (suppression of GH/IGF-1, tg/-) fed ad AL. Both CR and DF extend the median and maxim … More um lifespan by 10% and enhance insulin sensitivity as compared with (-/-) AL rats. In the present study, we investigated the influences of CR and DF in white adipose tissue to clarify key molecules for the beneficial action of CR including higher insulin sensitivity. Both CR and DF reduced blood insulin and leptin levels, and increased adiponectin level. In WAT, both CR and DF decreased mRNA level of leptin, but increased that of adiponectin. Over 25,000 genes were examined using DNA chips in CR rats and DF rats, and compared with control (-/-) AL rats. CR and DF modulated the expression of 672 (2.7%) genes and 210 (0.84%) genes as compared with AL (-/-) rats, respectively. Among these genes, however, only 34 genes (0.1%) were altered the expressions by both CR and DF with the similar manner, suggesting that CR and DF independently regulate the expression of genes in WAT. Particularly, CR enhanced the expression of genes involved in metabolism but reduced that of genes involved in extracellular matrix, cytoskeleton and inflammation. In addition, promoter analysis using Web tool suggested that promoter of certain genes, which are up-regulated by CR, possesses SREBP binding site. Western blot for SREBP-1 indicated that CR increases protein level of SREBP-1 but DF dose not in WAT. These findings suggest that SREBP-1, at least in part, regulates the CR-associated gene expression profile in WAT in a GH/IGF-1-independent manner. SREBP-1 might be one of key players for the beneficial action of CR. Less

热量限制（CR）是已知的最简单的实验操作，以延长寿命和延缓实验室啮齿动物的广泛的年龄相关的病理生理变化。确切的潜在机制仍然未知，但CR动物与长寿侏儒小鼠有许多共同特征，包括较小的体型，较低的血浆胰岛素和IGF-1水平以及较高的胰岛素敏感性。近年来，白色脂肪组织（WAT）被认为是一种内分泌器官，其功能障碍影响胰岛素敏感性、2型糖尿病的发病、并发症、衰老和寿命。为了阐明GH/IGF-1抑制和CR之间的关系，我们以前研究了自由采食（AL）或30%CR的雄性野生型（-/-）大鼠和携带反义GH转基因（GH/IGF-1抑制，tg/-）的杂合侏儒大鼠（DF）的生存和胰岛素敏感性。CR和DF延长了AD AL的中位数和最大值。 ...更多信息 与（-/-）AL大鼠相比，（-/-）AL大鼠的寿命延长10%，胰岛素敏感性增强。在本研究中，我们研究了CR和DF对白色脂肪组织的影响，以阐明CR有益作用的关键分子，包括更高的胰岛素敏感性。CR和DF均降低血胰岛素和瘦素水平，升高脂联素水平。在WAT模型中，CR和DF均降低瘦素的mRNA水平，但增加脂联素的mRNA水平。使用DNA芯片检测CR大鼠和DF大鼠的25，000多个基因，并与对照（-/-）AL大鼠进行比较。与AL（-/-）大鼠相比，CR和DF分别调节了672个（2.7%）和210个（0.84%）基因的表达。在这些基因中，只有34个基因（0.1%）的表达被CR和DF以相似的方式改变，这表明CR和DF独立地调节WAT中基因的表达。特别地，CR增强了参与代谢的基因的表达，但降低了参与细胞外基质、细胞骨架和炎症的基因的表达。此外，启动子分析表明，某些基因的启动子，这是CR上调，具有SREBP结合位点。Western blot结果显示，CR可提高WAT中SREBP-1蛋白水平，而DF对SREBP-1蛋白水平无影响。这些发现表明，SREBP-1，至少部分，调节CR相关基因的表达谱在WAT在GH/IGF-1的独立方式。SREBP-1可能是CR的有益作用的关键参与者之一。少

项目成果

Effect of leptin on hypothalamic gene expression in calorie-restricted rats

• DOI: 10.1093/gerona/61.9.890
• 发表时间: 2006-09-01
• 期刊: JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
• 影响因子: 5.1
• 作者: Komatsu, Toshimitsu;Chiba, Takuya;Shimokawa, Isao
• 通讯作者: Shimokawa, Isao

Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue

• DOI: 10.1093/jn/136.2.343
• 发表时间: 2006-02-01
• 期刊: JOURNAL OF NUTRITION
• 影响因子: 4.2
• 作者: Higami, Y;Barger, JL;Weindruch, R
• 通讯作者: Weindruch, R

Laboratory findings of caloric restriction in rodents and primates

啮齿动物和灵长类动物热量限制的实验室结果

• 发表时间: 2005
• 期刊: Adv Clin Chem 39
• 作者: Mizoshita;T.;Tsukamoto;T.;Nakanishi;H.;Inada;K.;Ogasawara;N.;Joh.;T.;Itoh;M.;Yamamura;Y.;Tatematsu;M.;Higami Y
• 通讯作者: Higami Y

Hepatic gene expression profile of lipid metabolism in rats : impact of caloric restriction and growth hormone/IGF-1 suppression.

大鼠脂质代谢的肝脏基因表达谱：热量限制和生长激素/IGF-1 抑制的影响。

• 期刊: J Gerontol A Biol Sci Med Sci in press
• 作者: Higami Y;Tsuchiya T;et al.
• 通讯作者: et al.

Acute stress response in calorie-restricted rats to lipopolysaccharide-induced inflammation

• DOI: 10.1016/j.mad.2004.11.007
• 发表时间: 2005-05-01
• 期刊: MECHANISMS OF AGEING AND DEVELOPMENT
• 影响因子: 5.3
• 作者: Tsuchiya, T;Higami, Y;Shimokawa, I
• 通讯作者: Shimokawa, I