Kumar Anil, Ren Yi, Sundaram Kumaran, Mu Jingyao, Sriwastva Mukesh K, Dryden Gerald W, Lei Chao, Zhang Lifeng, Yan Jun, Zhang Xiang, Park Juw Won, Merchant Michael L, Teng Yun, Zhang Huang-Ge
James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202, USA.
Department of Breast and Thyroid Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223300, China.
Theranostics. 2021 Feb 19;11(9):4061-4077. doi: 10.7150/thno.52558. eCollection 2021.
Diet manipulation is the basis for prevention of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance are not well understood. Here, as proof-of-concept, ginger-derived nanoparticles (GDNP) were used for studying molecular mechanisms underlying GDNP mediated prevention of high-fat diet induced insulin resistance. Ginger-derived nanoparticles (GDNP) were isolated from ginger roots and administered orally to C57BL/6 high-fat diet mice. Fecal exosomes released from intestinal epithelial cells (IECs) of PBS or GDNP treated high-fat diet (HFD) fed mice were isolated by differential centrifugation. A micro-RNA (miRNA) polymerase chain reaction (PCR) array was used to profile the exosomal miRs and miRs of interest were further analyzed by quantitative real time (RT) PCR. miR-375 or antisense-miR375 was packed into nanoparticles made from the lipids extracted from GDNP. Nanoparticles was fluorescent labeled for monitoring their trafficking route after oral administration. The effect of these nanoparticles on glucose and insulin response of mice was determined by glucose and insulin tolerance tests. We report that HFD feeding increased the expression of AhR and inhibited the expression of miR-375 and VAMP7. Treatment with orally administered ginger-derived nanoparticles (GDNP) resulted in reversing HFD mediated inhibition of the expression of miR-375 and VAMP7. miR-375 knockout mice exhibited impaired glucose homeostasis and insulin resistance. Induction of intracellular miR-375 led to inhibition of the expression of AhR and VAMP7 mediated exporting of miR-375 into intestinal epithelial exosomes where they were taken up by gut bacteria and inhibited the production of the AhR ligand indole. Intestinal exosomes can also traffic to the liver and be taken up by hepatocytes, leading to miR-375 mediated inhibition of hepatic AhR over-expression and inducing the expression of genes associated with the hepatic insulin response. Altogether, GDNP prevents high-fat diet-induced insulin resistance by miR-375 mediated inhibition of the aryl hydrocarbon receptor mediated pathways over activated by HFD feeding. Collectively our findings reveal that oral administration of GDNP to HFD mice improves host glucose tolerance and insulin response via regulating AhR expression by GDNP induced miR-375 and VAMP7.
饮食调控是预防肥胖和糖尿病的基础。介导基于饮食预防胰岛素抵抗的分子机制尚未完全明确。在此，作为概念验证，姜衍生纳米颗粒（GDNP）被用于研究GDNP介导预防高脂饮食诱导的胰岛素抵抗的分子机制。姜衍生纳米颗粒（GDNP）从姜根中分离出来，并口服给予C57BL/6高脂饮食小鼠。通过差速离心从PBS或GDNP处理的高脂饮食（HFD）喂养小鼠的肠上皮细胞（IECs）释放的粪便外泌体被分离出来。使用微RNA（miRNA）聚合酶链反应（PCR）阵列对外泌体miR进行分析，感兴趣的miR通过定量实时（RT）PCR进一步分析。miR-375或反义miR375被包装到由从GDNP提取的脂质制成的纳米颗粒中。纳米颗粒进行荧光标记以监测其口服给药后的运输途径。通过葡萄糖和胰岛素耐量试验确定这些纳米颗粒对小鼠葡萄糖和胰岛素反应的影响。我们报告高脂饮食喂养增加了芳烃受体（AhR）的表达并抑制了miR-375和囊泡相关膜蛋白7（VAMP7）的表达。口服给予姜衍生纳米颗粒（GDNP）治疗导致逆转高脂饮食介导的对miR-375和VAMP7表达的抑制。miR-375基因敲除小鼠表现出葡萄糖稳态受损和胰岛素抵抗。细胞内miR-375的诱导导致AhR和VAMP7介导的miR-375输出到肠上皮外泌体中的表达受到抑制，在那里它们被肠道细菌摄取并抑制AhR配体吲哚的产生。肠外泌体也可以运输到肝脏并被肝细胞摄取，导致miR-375介导的肝脏AhR过表达的抑制并诱导与肝脏胰岛素反应相关的基因的表达。总之，GDNP通过miR-375介导的对高脂饮食喂养过度激活的芳烃受体介导的途径的抑制来预防高脂饮食诱导的胰岛素抵抗。我们的研究结果共同表明，对高脂饮食小鼠口服给予GDNP通过GDNP诱导的miR-375和VAMP7调节AhR表达来改善宿主葡萄糖耐量和胰岛素反应。
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