School of Life Sciences, Faculty of Science, University of Technology Sydney, New South Wales, Australia.
Tuberculosis Research Program, Centenary Institute, Newtown, New South Wales, Australia.
Immunol Cell Biol. 2018 Jan;96(1):41-53. doi: 10.1111/imcb.1002. Epub 2017 Nov 23.
The cytokine Tumor Necrosis Factor Superfamily member 14, TNFSF14 (or LIGHT), is a controversial player in numerous diseases. We investigated the role of endogenously expressed TNFSF14 in diet-induced obesity in vivo. Firstly, we studied the effects of Tnfsf14 ablation on the development of obesity, glucose intolerance, insulin resistance, steatosis, tissue inflammation, and mitochondrial respiration in the liver. Secondly, we examined the role of TNFSF14 expression in hematopoietic cells on obesity and insulin sensitivity. Male Tnfsf14 knockout (KO) and wild type mice were fed chow or high fat diet (HFD) for 12 weeks and were assessed for weight gain, glucose intolerance, insulin resistance, hepatosteatosis, mitochondrial dysfunction, and cytokine expression. Wild-type mice were also reconstituted with bone marrow cells from Tnfsf14 knockout mice and were fed chow or HFD for 12 weeks. These mice were examined for weight gain and insulin resistance. HFD fed mice had elevated circulating levels of serum TNFSF14. Liver and white adipose tissue are potential sources of this elevated TNFSF14. Tnfsf14 deficient mice displayed increased obesity, glucose intolerance, insulin resistance, hepatosteatosis, and mitochondrial dysfunction compared to control mice on a HFD. Hepatic cytokine profiling pointed to a potential novel role of decreased IL-6 in the metabolic disturbances in obesogenic Tnfsf14 knockout mice. Bone marrow cells from Tnfsf14 deficient mice appeared to promote diet-induced obesity, insulin resistance and reduced FGF21 levels in white adipose tissue and liver. Our novel data suggest that Tnfsf14 ablation exacerbates parameters of the metabolic syndrome under high fat feeding conditions and provides evidence to support the development of TNFSF14 agonists as potential therapeutics in diet-induced obesity.
细胞因子肿瘤坏死因子超家族成员 14（TNFSF14，也称为 LIGHT）在许多疾病中是一个有争议的角色。我们研究了内源性表达的 TNFSF14 在体内饮食诱导肥胖中的作用。首先，我们研究了 Tnfsf14 缺失对肥胖、葡萄糖不耐受、胰岛素抵抗、脂肪变性、组织炎症和肝脏线粒体呼吸的发展的影响。其次，我们检查了 TNFSF14 在造血细胞中对肥胖和胰岛素敏感性的表达作用。雄性 Tnfsf14 敲除（KO）和野生型小鼠分别用标准饲料或高脂肪饮食（HFD）喂养 12 周，并评估体重增加、葡萄糖不耐受、胰岛素抵抗、肝脂肪变性、线粒体功能障碍和细胞因子表达。野生型小鼠还接受了 Tnfsf14 敲除小鼠的骨髓细胞重建，并分别用标准饲料或 HFD 喂养 12 周。这些小鼠评估体重增加和胰岛素抵抗情况。HFD 喂养的小鼠血清中 TNFSF14 水平升高。肝脏和白色脂肪组织是这种升高的 TNFSF14 的潜在来源。与 HFD 喂养的对照小鼠相比，Tnfsf14 缺乏的小鼠表现出更高的肥胖、葡萄糖不耐受、胰岛素抵抗、肝脂肪变性和线粒体功能障碍。肝细胞因子分析表明，在肥胖的 Tnfsf14 敲除小鼠的代谢紊乱中，IL-6 降低可能具有潜在的新作用。来自 Tnfsf14 缺乏的小鼠的骨髓细胞似乎促进了饮食诱导的肥胖、胰岛素抵抗以及白色脂肪组织和肝脏中 FGF21 水平的降低。我们的新数据表明，在高脂肪喂养条件下，Tnfsf14 缺失会加剧代谢综合征的参数，并为开发 TNFSF14 激动剂作为饮食诱导肥胖的潜在治疗方法提供证据支持。
