Contribution of CNS Sensing to HF Diet-Induced Obesity

University Of Cincinnati, Cincinnati OH

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Abstract

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