A female-specific neuroendocrine center controlling energy expenditure

项目总结/摘要 基本原理：中年女性的体重增加通常与女性体内雌激素水平下降有关。 更年期的开始激素替代疗法（HRT）可以抑制绝经后体重增加， 也会增加中风和乳腺癌的风险。了解雌激素反应神经元 调节身体活动和能量消耗可能会导致开发新的策略， 治疗女性肥胖症。 方法：我们已经建立了一个雌性肥胖小鼠模型，其中转录因子 使用Sf 1驱动的CRE重组酶，Nkx 2 -1在腹内侧下丘脑（VMH）中被消融， 1 Sf 1Cre小鼠。雌性而非雄性Nkx 2 - 1 Sf 1Cre小鼠肥胖，并表现出减少的体力活动， VMH中ER阳性神经元较少。我推测，雌激素反应的Nkx 2 -1神经元在 VMH调节雌性小鼠的身体活动，这些神经元的丢失是“沙发土豆”的基础。 在Nkx 2 - 1 Sf 1Cre雌性中观察到表型。在两个目标中，我将定义雌激素反应性Nkx 2 -1 VMH中的神经元调节身体活动，并决定它们是否足以拯救久坐不动的人。 移植到肥胖小鼠体内时的行为。 影响：Nkx 2 - 1 Sf 1Cre小鼠提供了一个独特的机会来定义性二态神经内分泌 调节身体活动的中心。拟议的研究应提供新的潜在战略， 减少久坐行为，改善女性的代谢健康。 环境：研究导师是冬青英格拉哈姆博士，在发展领域的领导者。 神经内分泌学约翰·鲁宾斯坦博士，艾利森·徐博士和艾伦·巴斯鲍姆博士同意在一个 咨询委员会提供专业科学知识和职业发展指导。在 除了研究训练，我建议在神经科学和负责任的行为教学课程， 的研究。 职业目标：我将参加在加州大学旧金山分校的职业发展研讨会， 学术研究总的来说，拟议的研究和职业发展培训活动将 准备让我成为肥胖研究领域的独立调查员。

PROJECT SUMMARY/ABSTRACT Rationale: Weight gain in middle-aged women often is associated with declining estrogen at the onset of menopause. Hormone replacement therapy (HRT) can curb postmenopausal weight gain but can also increase the risk of stroke and breast cancer. Understanding how estrogen-responsive neurons regulate physical activity and energy expenditure may lead to the development of novel strategies for treating obesity in women. Approach: We have developed a mouse model of female obesity in which the transcription factor Nkx2-1 is ablated in the ventromedial hypothalamus (VMH) using Sf1-driven CRE recombinase, Nkx2- 1Sf1Cre mice. Female but not male Nkx2-1Sf1Cre mice are obese and exhibit reduced physical activity and fewer ER¿-positive neurons in the VMH. I hypothesize that estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity in female mice and that loss of these neurons underlies the "couch-potato" phenotype observed in Nkx2-1Sf1Cre females. In two aims, I will define how estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity and determine if they are sufficient to rescue sedentary behavior when transplanted into obese mice. Impact: Nkx2-1Sf1Cre mice offer a unique opportunity to define a sexually dimorphic neuroendocrine center that regulates physical activity. The proposed studies should provide new potential strategies for decreasing sedentary behavior and improving metabolic health in women. Environment: The research mentor is Dr. Holly Ingraham, a leader in the field of developmental neuroendocrinology. Drs. John Rubenstein, Allison Xu, and Allan Basbaum have agreed to serve on an Advisory Committee to provide specialized scientific expertise and guidance in career development. In addition to research training, I propose didactic coursework in neuroscience and the responsible conduct of research. Career goals: I will participate in career development workshops at UCSF to prepare for a career in academic research. Overall, the proposed research and career development training activities will prepare me to become an independent investigator in the field of obesity research.