GPM6B基因的可变剪接转变调控白色脂肪棕色化及肥胖的作用与机制

白色脂肪棕色化是抵抗肥胖的有力手段。β3肾上腺素受体（β3-AR）功能活化可促进白色脂肪棕色化；而TGF-β-SMAD2/3通路可抑制白色脂肪棕色化。我们前期发现GPM6B可与TGF-β受体I（TβRI）结合激活TGF-β-SMAD2/3通路（Stem cells，2019），而GPM6B有6种跨膜蛋白亚型，究竟是哪种起作用尚未阐明。后续预实验发现，冷诱导的棕色化中GPM6B发生变异体2向6的可变剪接转变，而肥胖时这种转变受到抑制；变异体6编码的蛋白亚型5可与β3-AR结合，变异体2编码的蛋白亚型2可与TβRI结合。本研究拟揭示GPM6B变异体2向6的可变剪接转变促进白色脂肪棕色化的作用，明确这两个mRNA变异体编码的两个不同的蛋白亚型分别作为TβRI和β3-AR细胞受体调节蛋白起作用的机制，确证改变GPM6B异常可变剪接对肥胖的改善作用，为从改变mRNA可变剪接的角度防治肥胖提供新靶点。

Obesity, an increasingly serious worldwide health concern, develops when energy intake exceeds energy expenditure. Therefore, as a strategy to increase energy expenditure, stimulating white adipose browning represents an attractive concept for combating obesity and associated metabolic diseases. β3-adrenergic stimulation is responsible for white adipose browning during cold acclimation. Studies have shown that blockade of TGF-β-Smad2/3 signaling induces white adipose browning. Our recent studies have demonstrated that GPM6B interacted with TβRI to activate TGF-β-Smad2/3 signaling. But GPM6B has six transmembrane protein subtypes, and it is not clear which one can directly bind to TβRI. Our preliminary experimental results have clearly shown that GPM6B undergoes alternative splicing swtich from mRNA variant 2 to 6 in cold-induced browning, and this swtich is inhibited when obese. Moreover, we found that GPM6B protein subtype 5 encoded by mRNA variant 6 can bind to β3-AR and protein subtype 2 encoded by mRNA variant 2 can bind to TβRI. This study will elucidate the role and mechanism of GPM6B alternative splicing swtich in adipose tissue browning and obesity, providing new therapeutic strategies for the prevention and treatment of obesity and and its comorbidities.