Transgenic Expression Of Nsaid-Activated Gene-1 (Nag-1) Protects Mice From High Fat Diet-Induced Obesity

Previously, we generated transgenic mice which over-express human NAG-1/GDF15 gene. These mice are resistant to the development of colorectal cancer and have reduced responses to inflammatory stimuli. In the present study, we observed that NAG-1 transgenic mice (NAG-1 Tg) are smaller and leaner than their wild-type counterparts and have less abdominal fat despite comparable food intake. Interestingly, the transgenic mice have lower circulating levels of the inflammatory adipokine, leptin, and lower expression in abdominal fat, the major source of leptin. Placed on a high fat diet (60% fat), body weight gain in NAG-1 Tg mice is very small or negligible compared to wild-type mice. Analysis of the metabolic activity showed that NAG-1 Tg mice on the high fat diet have higher energy expenditure than WT mice. In addition, global gene expression profiling analysis showed that expression of several genes involved in lipid metabolism were significantly down-regulated in the liver of NAG-1 Tg mice. Real-time PCR analysis confirmed decreased expression of genes such as Cidea, Cidec, Mogat1, CD36, and Apoa4, while the expression of SIRT-1 and phosphorylated SIRT-1 was not altered in the NAG-1 Tg mice. Taken together, our data indicate increased energy expenditure and decreased expression of lipid metabolism genes have pivotal roles for the lower observed abdominal fat levels. Furthermore, lower leptin levels, a critical mediator of intestinal inflammation, found in NAG-1 transgenic mice, may contribute to lower intestinal tumor growth and reduced inflammatory responses reported for the NAG-1 Tg mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 982. doi:10.1158/1538-7445.AM2011-982