甲状旁腺激素通过SIK2/ChREBP调控白色脂肪组织棕色化的机制研究

原发性甲状旁腺功能亢进症（PHPT）是以甲状旁腺激素（PTH）自主过度分泌为中心的内分泌系统第三大常见疾病，探索PTH的病理生理作用成为理解该疾病的核心。申请人在临床工作中观察到PHPT患者BMI随PTH升高而显著降低的现像，引发了对于PTH是否会作用于脂肪并调控能量代谢的思考。申请人在前期工作中构建模拟PHPT的小鼠模型，该小鼠体重体脂下降、代谢率增高、白色脂肪棕色化，提示PTH可能通过促进脂肪棕色化而降低体重；全转录组测序发现ChREBP可能是该小鼠脂肪棕色化的重要中介分子，而近年发现SIK2是ChREBP的重要调控因子，且SIK2活性受到PTH受体下游通路的调控，因而本研究从多层面探讨PTH通过SIK2/ChREBP通路促进白色脂肪组织棕色化并调控能量代谢的机制。本研究拓展了PTH作为经典的钙磷代谢激素的内涵，丰富了临床医生对PHPT疾病的认识，为寻找肥胖症的治疗靶点提供新视角。

Primary hyperparathyroidism (PHPT) is the third most common endocrine disease characterized by the uncontrolled secretion of parathyroid hormone(PTH). Exploring the pathophysiological effect of PTH turns to be the key point in understanding PHPT. Interestingly, we recently observed in our clinical practice that PTH was negatively associated with BMI, promoting us to ask whether PTH could act on adipose tissue and regulate the energy metabolim. In our preliminary work, a mouse model mimicking PHPT was built and it showed reduced body weight, reduced body fat content with increased metabolic rate and white adipose tissue browning, indicating that PTH negatively regulates energy balance through promoting adipose tissue browning . The result from PHPT RNA seq indicates that ChREBP might be a key factor in the browning process of PHPT. Recently, it was reported that SIK2 is one of important factors in regulating ChREBP. Meanwhile, the activity of SIK2 is controlled by the PTH receptor and its downstream signaling. Thus, this study was aimed to show that PTH promotes white adipose tissue browning and energy metabolism through SIK2/ChREBP pathway. This work provides a new insight into the effect of the classical calcium regulating parathyroid hormone， provides new knowledge of the PHPT， and will be promising in fighting against the obesity.