基于非瘦素体重调节理论的肥胖症动力学模拟及实验研究

Obesity has become a major threat to human health. It was envisioned that the brain, via sampling information carried by the hormone leptin, tightly regulates the body weight; and obesity is caused by leptin resistance (the brain becomes insensitive to leptin signaling). Although lacking strong evidences and having various problems, the theory of leptin mediated weight regulation, facing no competitions from other theories, has been widely accepted. The PI, on the basis of previous works, put forward a non-leptin theory that can plausibly explain weight stability and its slow increase, and ultimately the prevalence of obesity. We propose to test the hypothesis through dynamical modeling (simulation of plasma glucose and insulin dynamics by ODEs, GPU parallel computation to simulate insulin mediated metabolism and growth of myocytes and adipocytes) and molecular biological experiments (fluorescence detection for measuring glucose influx into the cell, insulin resistance generation by small interfering RNA). We will study self adaptive growth of adipocytes and homeostasis of total fat in the body, elucidate the positive feedback mechanism between obesity and insulin resistance. The project would change the mindset of people that weight must be regulated by leptin. The success of the present project would provide valuable insights into weight reduction and generate optimal strategies for obesity treatments. The project thus has profound scientific and social values.

肥胖给人类的健康带来了巨大的威胁。传统观点认为大脑通过瘦素感知体内脂肪总量并得以调节体重而使之恒定；肥胖则是瘦素抵抗（大脑变得对瘦素不敏感）的结果。由于缺乏与之相竞争的理论，体重的瘦素调节被广泛接受，即使该理论证据不足且问题诸多。负责人在已有工作之基础上，提出了一个非瘦素理论，可以合理地解释体重的稳定及其缓慢的攀升，有望最终解开肥胖流行之谜。本项目将通过动力学模拟（微分方程刻画血糖及胰岛素动态变化、GPU并行计算模拟肌肉和脂肪细胞在胰岛素介导下的代谢和生长）和分子生物实验（细胞血糖提取的荧光检测、干扰小RNA产生胰岛素抵抗、等等）两方面来验证和修正非瘦素体重调节理论，揭示脂肪细胞的自适应生长和体内脂肪总量的动态平衡，阐明肥胖与胰岛素抵抗的正反馈互促机制。本项目突破了体重一定由瘦素调节这个思维定势；其圆满完成将为减肥提供新的思路，为肥胖症患者优化治疗干预策略；具有深远的科学意义和社会价值。

肥胖给人类的健康带来了巨大的威胁。传统观点认为大脑通过瘦素感知体内脂肪总量并得以调节体重而使之恒定；肥胖则是瘦素抵抗（大脑变得对瘦素不敏感）的结果。由于缺乏与之相竞争的理论，体重的瘦素调节被广泛接受，即使该理论证据不足且问题诸多。在本项目中，负责人提出了一个非瘦素理论（称作“代谢欧姆定律”），可以合理地解释体重的稳定及其缓慢的攀升，有望最终解开肥胖流行之谜。本项目通过动力学模拟（微分方程刻画血糖及胰岛素动态变化、GPU并行计算模拟肌肉和脂肪细胞在胰岛素介导下的代谢和生长）和分子生物实验（细胞血糖提取的荧光检测、干扰小RNA产生胰岛素抵抗、等等）两方面来验证和修正代谢欧姆定律，揭示脂肪细胞的自适应生长和体内脂肪总量的动态平衡，阐明肥胖与胰岛素抵抗的正反馈互促机制。本项目突破了体重一定由瘦素调节这个思维定势；它的圆满完成为减肥提供新的思路，为肥胖症患者优化治疗干预策略；具有深远的科学意义和社会价值。