A female-specific neuroendocrine center controlling energy expenditure

说明(申请人提供)：理由：中年女性体重增加通常与绝经初期雌激素水平下降有关。激素替代疗法(HRT)可以抑制绝经后体重增加，但也会增加中风和乳腺癌的风险。了解雌激素反应神经元如何调节身体活动和能量消耗，可能会导致开发治疗女性肥胖症的新策略。方法：我们建立了一种雌性肥胖小鼠模型，其中转录因子Nkx2-1在下丘脑腹内侧部(VMH)被消融，使用SF1驱动的Cre重组酶Nkx2-1Sf1Cre小鼠。雌性而不是雄性Nkx2-1Sf1Cre小鼠肥胖，体力活动减少，下丘脑室旁核ER�阳性神经元减少。我推测，VMH中雌激素反应的Nkx2-1神经元调节雌性小鼠的身体活动，这些神经元的丢失是在Nkx2-1Sf1Cre雌性小鼠中观察到的“沙发土豆”表型的基础。在两个目标中，我将定义VMH中对雌激素反应的Nkx2-1神经元如何调节身体活动，并确定它们是否足以在移植到肥胖小鼠身上时挽救久坐行为。影响：Nkx2-1Sf1Cre小鼠提供了一个独特的机会来定义一个调节身体活动的性二态神经内分泌中心。建议的研究应该为减少女性久坐行为和改善代谢健康提供新的潜在策略。环境：研究导师是霍莉·英格拉汉姆博士，她是发育神经内分泌学领域的领导者。John Rubenstein博士、Allison Xu博士和Allan Basbaum博士已同意在一个咨询委员会任职，该委员会将在职业发展方面提供专业的科学专业知识和指导。除了研究培训，我还建议在神经科学和负责任的研究方面进行教学课程。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，为从事学术研究做准备。总体而言，拟议的研究和职业发展培训活动将为我成为肥胖研究领域的独立调查员做好准备。

DESCRIPTION (provided by applicant):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.