Deletion of the FAT10 Gene Alters Energy Homeostasis in Mice.
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 ... read moretissue (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
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.read less