Contribution of CNS Sensing to HF Diet-Induced Obesity

在正常情况下，哺乳动物准确地匹配他们的热量摄入和热量消耗 这种匹配关键地涉及到下丘脑中控制食物摄入和 新陈代谢.这些下丘脑回路的活动受到外周信号的仔细调节， 反映了脂肪组织的数量我们的数据表明，中枢神经系统变得相对耐药 当大鼠被置于这些高饱和脂肪饮食中时，这些“肥胖信号”在CNS中的作用。 因此，本项目的总体目标是阐明导致 这种中枢神经系统对肥胖信号的抵抗。第一个目标是比较维持高饱和脂肪的大鼠 饮食对维持高单不饱和脂肪饮食的人来说是一个很好的选择。此外，我们将 确定观察到的CNS阻力是否与肥胖信号无法驱动 下丘脑中特定基因表达的变化。 越来越多的数据表明，这些下丘脑回路也直接感知可用的燃料， 类似于外周细胞类型的机制。因此，我们还将评估特定的代谢 暴露于高饱和和单不饱和饮食会改变CNS中的代谢途径。一 通过暴露于高脂肪而在β细胞中受损的途径是丙酮酸循环。因此，第二个具体 aim将确定下丘脑中丙酮酸循环减少对体重增加的贡献， 高饱和脂肪饮食产生的中枢神经系统抵抗。另一个关键的燃料敏感信号通路 是非典型激酶mTOR。初步数据表明，mTOR在 下丘脑调节食物摄入，因此我们最终的具体目标将评估减少的贡献。 mTOR活性和对高饱和脂肪饮食产生的体重增加和CMS抗性的作用。 这些实验将为特定的饮食变量如何影响关键电路提供相当多的线索 在下丘脑，从而导致重要的见解的病因和治疗常见的 在美国的成人和儿童人群中，

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.