A female-specific neuroendocrine center controlling energy expenditure

项目摘要/摘要 理由：中年女性体重增加通常与雌激素水平下降有关。 绝经期的到来。激素替代疗法(HRT)可以抑制绝经后体重增加，但 还会增加中风和乳腺癌的风险。了解雌激素反应神经元是如何 调节体力活动和能量消耗可能会导致制定新的战略 治疗女性肥胖症。 方法：我们建立了一种雌性肥胖小鼠模型，在该模型中，转录因子 使用SF1驱动的Cre重组酶Nkx2-1在下丘脑腹内侧(VMH)消融Nkx2-1。 1Sf1Cre小鼠。雌性而不是雄性Nkx2-1Sf1Cre小鼠肥胖，体力活动减少， VMH内ER阳性神经元较少。我假设雌激素反应的Nkx2-1神经元在 VMH调节雌性小鼠身体活动，而这些神经元的丧失是造成这种“沙发土豆”的原因 在Nkx2-1Sf1Cre女性中观察到表型。在两个目标中，我将定义雌激素反应Nkx2-1如何 VMH中的神经元调节身体活动，并确定它们是否足以挽救久坐不动的状态 移植到肥胖小鼠体内时的行为。 影响：Nkx2-1Sf1Cre小鼠提供了一个独特的机会来定义性二态神经内分泌 调节体力活动的中心。拟议的研究应为以下方面提供新的潜在战略 减少女性久坐行为，改善代谢健康。 环境：研究导师是霍莉·英格拉汉姆博士，她是发展领域的领导者 神经内分泌学。约翰·鲁宾斯坦博士、艾莉森·徐博士和艾伦·巴斯鲍姆博士同意在 咨询委员会在职业发展方面提供专门的科学专门知识和指导。在……里面 除了研究培训，我建议在神经科学和负责任的行为方面进行教学课程 研究的成果。 职业目标：我将参加加州大学旧金山分校的职业发展研讨会，为未来的职业生涯做准备 学术研究。总的来说，拟议的研究和职业发展培训活动将 让我做好准备，成为肥胖研究领域的一名独立调查员。

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.