Under normal circumstances, mammals accurately match their caloric intake to their caloric expenditure and this matching critically involves circuits in the hypothalamus that control both food intake and metabolism. The activity of these hypothalamic circuits is carefully regulated by peripheral signals that reflect the amount of adipose tissue. Our data indicate that the CNS becomes relatively resistant to the actions of these """"""""adiposity signals"""""""" in the CNS when rats are placed on these high-saturated fat diets. Thus, the overall goal of this project is to elucidate the molecular and metabolic mechanisms that cause this CNS resistance to adiposity signals.
The first aim will compare rats maintained on a high saturated fat diet to those maintained on a high mono unsaturated fat diet for such CNS resistance. Further, we will determine whether observed CNS resistance is associated with an inability for adiposity signals to drive changes in the expression of specific genes in the hypothalamus. Growing data indicate that these hypothalamic circuits also directly sense available fuel using mechanisms similar to peripheral cell types. As a result we will also assess how specific metabolic pathways in the CNS are altered by exposure to high saturated and mono unsaturated diets. One pathway that is impaired in beta-cells by exposure to high fat is the pyruvate cycle. Thus, the second specific aim will determine the contribution of reduced pyruvate cycling in the hypothalamus to the weight gain and CNS resistance produced by the high saturated fat diet. Another critical fuel sensitive signaling pathway in peripheral cell types is the atypical kinase mTOR. Preliminary data indicate a role for mTOR in the hypothalamus to regulate food intake and so our final specific aim will assess the contribution of reduced mTOR activity and action to the weight gain and CMS resistance produced by the high saturated fat diet. These experiments will shed considerable light on how specific dietary variables influence critical circuits in the hypothalamus and thereby lead to important insights about the etiology and treatment for common forms of obesity that continue to increase in both adult and pediatric populations in the U.S.
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