The role of the phosphatidylserine receptor Brain-specific angiogenesis inhibitor 1 (BAI1) in diet induced obesity

全世界有超过20亿人超重或肥胖。这种情况需要新的治疗策略。饮食性肥胖的特点是内脏脂肪垫大量脂肪细胞死亡和组织重塑。目前尚不清楚死亡的脂肪细胞如何导致饮食诱导的肥胖和相关的代谢并发症。然而，如果死亡的脂肪细胞具有病理价值，促进它们的清除应该可以改善饮食引起的肥胖并发症。Ravichandran教授实验室的初步实验表明，磷脂酰丝氨酸受体脑特异性血管生成抑制剂1 （BAI1）介导小鼠对高脂肪饮食的反应。BAI1参与凋亡细胞的清除，但也与其他情况有关。我们假设BAI1同时在单核/巨噬细胞和脂肪细胞中表达，参与了死亡脂肪细胞的吞噬清除，并介导了脂肪细胞对高脂肪饮食的适应。通过启动子特异性敲除或过表达BAI1，我们将表征高脂饮食喂养过程中BAI1在单核/巨噬细胞和脂肪细胞中的作用。越来越多的研究表明，饮食性肥胖的病理是复杂的。我们希望在免疫功能和代谢的交叉点上解决BAI1在饮食性肥胖中的作用。由于细胞代谢和细胞功能密切相关，我们打算了解BAI1如何影响单核/巨噬细胞和脂肪细胞对高脂饲料喂养的反应。通过我们的努力，我们希望对BAI1在饮食性肥胖中脂肪细胞清除、磷脂酰丝氨酸感知和代谢功能的作用有新的认识。这些结果也将有助于评估干预脂肪细胞清除和BAI1活性水平的治疗潜力。如果我们确认了高脂饮食中BAI1的初步数据，我们将设计涉及BAI1的单域抗体，并测试其在肥胖治疗中的适用性。

More than 2 billion people worldwide are characterized as overweight or obese. This situation brings the need for novel therapeutic strategies. Diet induced obesity is characterized by massive adipocyte cell death and tissue remodeling in the visceral fat pad. It is unclear how dead adipocytes contribute to diet induced obesity and associated metabolic complications. However, if dead adipocytes have a pathological value, boosting their removal should ameliorate the complications of diet induced obesity. Preliminary experiments in the laboratory of Prof. Ravichandran have shown that the phosphatidylserine receptor brain-specific angiogenesis inhibitor 1 (BAI1) is mediating the response to high fat diet in mice. BAI1 is involved in the clearance of apoptotic cells, but has also been implicated in other settings as well. Being expressed by both monocytes/macrophages and adipocytes, we hypothesize that BAI1 is involved in the phagocytic removal of dead adipocytes and mediates adaption of adipocytes to high fat diet. By deploying promoter-specific knockout or overexpression of BAI1, we will characterize the role of BAI1 in monocytes/macrophages and adipocytes during feeding with high fat diet.An increasing number of studies indicates that the pathology of diet induced obesity is complex. We wish to address the role of BAI1 during diet induced obesity at the intersection of immune function and metabolism. Since cell metabolism and cell function are closely linked, we intend to understand how BAI1 influences the action of monocytes/macrophages and adipocytes in response to feeding with high fat diet. With our efforts, we aim to obtain new insights into the role of adipocyte clearance, phosphatidylserine sensing, and metabolic functions of BAI1 in diet induced obesity. These results will also help to assess the therapeutic potential of interfering at the level of adipocyte clearance and BAI1 activity. If we confirm the preliminary data on BAI1 during high fat diet, we will design single-domain antibodies engaging BAI1 and test their applicability for treatment of obesity.