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

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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