Department of Infectious Diseases, University of Georgia, Athens, GA, United States.
Department of Pathology, University of Georgia, Athens, GA, United States.
Front Immunol. 2021 May 20;12:668217. doi: 10.3389/fimmu.2021.668217. eCollection 2021.
Obesity is the largest risk factor for the development of chronic diseases in industrialized countries. Excessive fat accumulation triggers a state of chronic low-grade inflammation to the detriment of numerous organs. To address this problem, our lab has been examining the anti-inflammatory mechanisms of two human milk oligosaccharides (HMOs), lacto-N-fucopentaose III (LNFPIII) and lacto-N-neotetraose (LNnT). LNFPIII and LNnT are HMOs that differ in structure presence/absence of an α1,3-linked fucose. We utilize LNFPIII and LNnT in conjugate form, where 10-12 molecules of LNFPIII or LNnT are conjugated to a 40 kDa dextran carrier (P3DEX/NTDEX). Previous studies from our lab have shown that LNFPIII conjugates are anti-inflammatory, act on multiple cell types, and are therapeutic in a wide range of murine inflammatory disease models. The α1,3-linked fucose residue on LNFPIII makes it difficult and more expensive to synthesize. Therefore, we asked if LNnT conjugates induced similar therapeutic effects to LNFPIII. Herein, we compare the therapeutic effects of P3DEX and NTDEX in a model of diet-induced obesity (DIO). Male mice were placed on a high-fat diet for six weeks and then injected twice per week for eight weeks with 25µg of 40 kDa dextran (DEX; vehicle control), P3DEX, or NTDEX. We found that treatment with P3DEX, but not NTDEX, led to reductions in body weight, adipose tissue (AT) weights, and fasting blood glucose levels. Mice treated with P3DEX also demonstrated improvements in glucose homeostasis and insulin tolerance. Treatment with P3DEX or NTDEX also induced different profiles of serum chemokines, cytokines, adipokines, and incretin hormones, with P3DEX notably reducing circulating levels of leptin and resistin. P3DEX also reduced WAT inflammation and hepatic lipid accumulation, whereas NTDEX seemed to worsen these parameters. These results suggest that the small structural difference between P3DEX and NTDEX has significant effects on the conjugates' therapeutic abilities. Future work will focus on identifying the receptors for these conjugates and delineating the mechanisms by which P3DEX and NTDEX exert their effects.
肥胖是工业化国家慢性病发展的最大风险因素。过多的脂肪积累会引发慢性低度炎症，从而损害众多器官。为了解决这个问题，我们的实验室一直在研究两种人乳寡糖（HMOs）——乳-N-岩藻糖基戊糖 III（LNFPIII）和乳-N-新戊糖基四糖（LNnT）的抗炎机制。LNFPIII 和 LNnT 在结构上有所不同，存在/不存在 α1,3 连接的岩藻糖。我们使用 LNFPIII 和 LNnT 的缀合形式，其中 10-12 个 LNFPIII 或 LNnT 分子与 40 kDa 葡聚糖载体（P3DEX/NTDEX）缀合。我们实验室之前的研究表明，LNFPIII 缀合物具有抗炎作用，作用于多种细胞类型，并且在广泛的小鼠炎症性疾病模型中具有治疗作用。LNFPIII 上的 α1,3 连接的岩藻糖残基使其合成变得困难且昂贵。因此，我们想知道 LNnT 缀合物是否会引起与 LNFPIII 相似的治疗效果。在这里，我们在饮食诱导肥胖（DIO）模型中比较了 P3DEX 和 NTDEX 的治疗效果。雄性小鼠接受高脂饮食六周，然后每周两次注射 25µg 40 kDa 葡聚糖（DEX；载体对照）、P3DEX 或 NTDEX 共八周。我们发现，用 P3DEX 治疗而不是 NTDEX 治疗可降低体重、脂肪组织（AT）重量和空腹血糖水平。用 P3DEX 治疗的小鼠还表现出葡萄糖稳态和胰岛素耐量的改善。用 P3DEX 或 NTDEX 治疗还诱导了不同的血清趋化因子、细胞因子、脂肪因子和肠促胰岛素激素谱，其中 P3DEX 显著降低了循环瘦素和抵抗素水平。P3DEX 还降低了 WAT 炎症和肝脂质积累，而 NTDEX 似乎使这些参数恶化。这些结果表明，P3DEX 和 NTDEX 之间的微小结构差异对缀合物的治疗能力有显著影响。未来的工作将集中于鉴定这些缀合物的受体，并阐明 P3DEX 和 NTDEX 发挥作用的机制。
