Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice复制标题

白细胞介素-1 α 缺乏可减少饮食诱导肥胖小鼠的肥胖、葡萄糖耐受不良和肝脏新生脂肪生成

Interleukin (IL)-1α and IL-1β, the main agonists of the IL-1 family of cytokines, stimulate the expression of a range of inflammatory genes. IL-1α, IL-1β and the specific receptor antagonist (IL-1Ra) exert their effects on binding to IL-1 receptor type 1 (IL-1R1). IL-1α and IL-1β are synthesized as precursors and their processing to mature forms requires specific cellular proteases. In contrast to IL-1β, which is only active as a mature secreted molecule after cleavage by caspase-1, IL-1α exerts its effects both in the mature and the precursor forms when binding to IL-1R1. IL-1α belongs to a newly recognized group of dual-function cytokines that play a role in sterile inflammation and tissue remodeling. Non-immune cells constitutively express low levels of IL-1α protein. Following an apoptotic stimuli, the IL-1α precursor translocates to the nucleus, binds to chromatin and is retained in the cells. Necrosis of cells releases IL-1α, which serves as a “danger signal” by binding to IL-1R1 on neighboring cells to induce sterile inflammation manifested by recruitment of inflammatory cells. The secretion of IL-1α can also be a regulated process and is either inflammasome/ caspase-1 dependent or independent. While the role of IL-1β, IL-1R1 and IL-1Ra in obesity and IR was investigated, the role of IL-1α was scarcely studied. Gene deletion of the inflammasome components, which regulate the activity of IL-1β, either prevented obesity and/ or reduced obesity-induced IR and hepatic steatosis. In addition, IL-1β deficiency increased adipose tissue expandability yet with reduced inflammation and reduced fat accumulation in the liver. Lack of IL-1R1 itself also protected against high-fat diet (HFD)-induced IR despite immune cell recruitment but with reduced local adipose tissue inflammation. Administration of IL-1Ra to obese mice markedly reduced steatosis and hepatic lipogenic gene expression demonstrating that IL-1β signaling upregulates hepatic lipogenesis in obesity. Moreover, IL-1Ra seems to contribute to the development of IR in a mechanism independent of IL-1Ra binding to IL-1R1. The pro-atherogenic role of IL-1α and specifically bone marrow-derived IL-1α was reported by us and confirmed by work from another laboratory. Recently, a few reports suggested a possible role of IL-1α in obesity-associated comorbidities. A functional polymorphism of IL-1α and its potential role in obesity in humans and mice was reported. In addition, IL-1α was shown to be important in immune cell recruitment following the injection of endogenous oils isolated from human adipocytes into mouse peritoneum. Although these reports suggest the involvement of IL-1α in obesity, there are no studies that directly addressed its role in diet-induced obesity. Therefore, in this work, we studied the effect of IL-1α deficiency on diet-induced obesity in mice.

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