Increasing energy expenditure via induction of browning in white adipose tissue has emerged as a potential strategy to treat obesity and associated metabolic complications. We previously reported that ASK1 inhibition in adipocytes protected from high-fat diet (HFD) or lipopolysaccharide (LPS)-mediated downregulation of UCP1 both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression attenuated cold-induction of UCP-1 in inguinal fat. Herein, we provide evidence that both TNFα-mediated and HFD-induced activation of p38 MAPK in white adipocytes are ASK1-dependent. Moreover, expression of senescence markers was reduced in HFD-fed adipocyte-specific ASK1 knockout mice. Similarly, LPS-induced upregulation of senescence markers was blunted in ASK1-depleted adipocytes. Thus, our study identifies a previously unknown role for ASK1 in the induction of stress-induced senescence.

通过诱导白色脂肪组织中的褐变来增加能量消耗已成为治疗肥胖症和相关代谢并发症的潜在策略。我们先前曾报道，在体外和体内，高脂饮食（HFD）或脂多糖（LPS）介导的UCP1下调保护的脂肪细胞中的ASK1抑制作用。相反，脂肪细胞特异性ASK1过表达减弱了腹股沟脂肪中UCP-1的冷诱导。在本文中，我们提供证据表明，白色脂肪细胞中TNFα介导和HFD诱导的p38 MAPK激活均与ASK1有关。此外，衰老标志物的表达在喂食HFD的脂肪细胞特异性ASK1基因敲除小鼠中降低。同样，LPS诱导的衰老标记的上调在ASK1缺失的脂肪细胞中减弱了。因此，我们的研究确定了ASK1在诱导应激性衰老中的未知作用。