%0 PDF %T Deletion of the FAT10 Gene Alters Energy Homeostasis in Mice. %A DeFuria, Jason. %8 2017-04-14 %R http://localhost/files/z316qc930 %X Abstract: ABSTRACT Chronic increased caloric intake without concomitant increases in energy metabolism result in obesity. The rise in obesity in the US can be attributed to over-nutrition and a sedentary lifestyle. Understanding nutritional and genetic factors that promote energy metabolism are critical for combating obesity and associated disorders and maintain overall health. Muscle, adipose tissue (AT), liver and the pancreas respond to nutrient intake and establish inter-tissue communication via release of circulating signaling factors including hormones (e.g. insulin from the pancreas) and fatty acids (from AT). These processes promote balanced energy storage and use, known collectively as energy homeostasis. Over-nutrition and/or poor diet can disturb normal energy homeostasis promoting obesity and associated complications such as insulin resistance. The Human Leukocyte Antigen (HLA) F&ndashadjacent transcript 10 (FAT10) is an emerging player in regulation of energy homeostasis. FAT10 has been implicated in chronic diseases such as Type I Diabetes, cancer and genetic lipodystrophies. In these pathologies, energy homeostasis has been altered due to genetic mutations. Fat10 is expressed in a variety of insulin sensitive tissues including liver, muscle, adipose as well as the pancreas. We hypothesize that ablation of the FAT10 gene will alter systemic energy metabolism. This thesis work demonstrates the major finding that genetic deletion of the FAT10 gene in mice alters energy homeostasis and significantly decreases adipose mass through increases in AT and muscle catabolism. In mice fed a normal diet, we demonstrate that FAT10 is expressed during normal AT growth. FAT10 KO mice have reduced adiposity and burn more calories (enhanced energy expenditure) compared to WT mice without decreasing caloric intake or increasing exercise. Using indirect calorimetry, we demonstrate that FAT10 KO mice preferentially burn lipid. Skeletal muscle exhibits increased expression of lipid burning genes. This response appears to be due to increased circulating fatty acids derived from AT release (lipolysis). FAT10 KO mice have constitutively low circulating insulin that may be permissive for the observed enhanced adipose tissue lipolysis. This model suggests that increases in lipolysis are due to decreases in available circulating insulin. The enhanced lipid burning in muscle is in response to the fatty acid load in the blood from AT lipolysis. When FAT10 KO and WT mice were fed a high fat diet, the KO mice retained mildly enhanced energy expenditure and became obese at a slower rate compared to WT mice fed the same diet. Interestingly, FAT10 KO mice on a HFD remained insulin sensitive. Altering lipid content of the diet to primarily saturated fat diminishes the hypermetabolic phenotype. This thesis work indicates that FAT10 is a novel gene involved in the regulation of systemic energy metabolism that may be dependent on the fatty acid composition of the diet. Because the FAT10 gene was absent from all tissues, it is not possible to identify the tissue influencing the increased energy metabolism. This point warrants further dissection by tissue specific ablation of the FAT10 gene to identify how FAT10 affects systemic energy metabolism. Additionally, since FAT10 is associated with increased risk for chronic disease (diabetes, cancer, HIV associated nephropathy) and is interactive with key cellular regulators (p53 and NF&kappaB), this research opens new avenues for further investigation of the tissue-specific biological function of FAT10.; Thesis (Ph.D.)--Tufts University, 2011.; Submitted to the Dept. of Biochemical and Molecular Nutrition.; Advisor: Martin Obin.; Committee: Andrew Greenberg, Sang Woon Choi, and Xiang-Dong Wang.; Keywords: Nutrition, Molecular biology, and Physiology. %[ 2022-10-11 %9 Text %~ Tufts Digital Library %W Institution