Contribution of CNS Sensing to HF Diet-Induced Obesity

在正常情况下，哺乳动物会准确地将其卡路里摄入量与卡路里消耗相匹配 关键的是，这种匹配涉及下丘脑中控制食物摄入量和 新陈代谢。这些下丘脑回路的活动受到外围信号的仔细调节，这些信号 反映脂肪组织的数量。我们的数据表明，中枢神经系统对 当大鼠摄入这些高饱和脂肪食物时，这些“肥胖信号”在中枢神经系统中的作用。 因此，这个项目的总体目标是阐明导致 这种中枢神经系统抵抗肥胖的信号。第一个目标是比较摄入高饱和脂肪的大鼠。 对于那些保持高单一不饱和脂肪饮食的人来说，这种中枢神经系统抵抗。此外，我们还将 确定观察到的中枢神经系统抵抗是否与肥胖信号无法驱动有关 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觉到可用的燃料使用 机制类似于外周细胞类型。因此，我们还将评估特定的代谢 中枢神经系统中的通路会因接触高饱和和单不饱和饮食而改变。一 暴露在高脂肪环境中的β细胞受损的途径是丙酮酸循环。因此，第二个具体 AIM将确定下丘脑丙酮酸循环减少对体重增加的贡献 高饱和脂肪饮食所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 在外周细胞类型中有一种非典型的激酶mTOR。初步数据表明，mTOR在 下丘脑调节食物的摄入量，所以我们最终的具体目标是评估减少 MTOR活性及其对高饱和脂肪饮食所产生的体重增加和CMS抵抗的作用。 这些实验将阐明特定的饮食变量是如何影响关键回路的。 从而对常见脑病的病因和治疗有了重要的认识。 肥胖形式在美国成人和儿童人口中持续增加。

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.