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Theranostics 2021; 11(9):4061-4077. doi:10.7150/thno.52558 This issue Cite

Research Paper

miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene

Anil Kumar1*, Yi Ren2*, Kumaran Sundaram1, Jingyao Mu1, Mukesh K Sriwastva1, Gerald W Dryden1,3, Chao Lei1, Lifeng Zhang1, Jun Yan1, Xiang Zhang4, Juw Won Park5,6, Michael L Merchant7, Yun Teng1✉, Huang-Ge Zhang1,8✉

1. James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202, USA.
2. Department of Breast and Thyroid Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223300, China.
3. Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
4. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
5. Department of Computer Engineering and Computer Science, University of Louisville, KY 40202, USA.
6. KBRIN Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA.
7. Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA.
8. Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA.
* These authors contributed equally to this work.

✉ Corresponding authors: Dr. Huang-Ge Zhang, James Graham Brown Cancer Center, University of Louisville, CTRB 309, 505 Hancock Street, Louisville, KY 40202; E-mail address: h0zhan17edu or yun.tengedu

Citation:
Kumar A, Ren Y, Sundaram K, Mu J, Sriwastva MK, Dryden GW, Lei C, Zhang L, Yan J, Zhang X, Park JW, Merchant ML, Teng Y, Zhang HG. miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics 2021; 11(9):4061-4077. doi:10.7150/thno.52558. https://www.thno.org/v11p4061.htm
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Abstract

Graphic abstract

Background: 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.

Methods: 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 in vivo 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.

Results: 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.

Conclusion: 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.

Keywords: Ginger derived nanoparticles, AhR, VAMP7, Exosomes, miR-375, E. coli tryptophanase (tnaA), indole, gut/liver axis, insulin resistance.

Citation styles

APA
Kumar, A., Ren, Y., Sundaram, K., Mu, J., Sriwastva, M.K., Dryden, G.W., Lei, C., Zhang, L., Yan, J., Zhang, X., Park, J.W., Merchant, M.L., Teng, Y., Zhang, H.G. (2021). miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics, 11(9), 4061-4077. https://doi.org/10.7150/thno.52558.

ACS
Kumar, A.; Ren, Y.; Sundaram, K.; Mu, J.; Sriwastva, M.K.; Dryden, G.W.; Lei, C.; Zhang, L.; Yan, J.; Zhang, X.; Park, J.W.; Merchant, M.L.; Teng, Y.; Zhang, H.G. miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics 2021, 11 (9), 4061-4077. DOI: 10.7150/thno.52558.

NLM
Kumar A, Ren Y, Sundaram K, Mu J, Sriwastva MK, Dryden GW, Lei C, Zhang L, Yan J, Zhang X, Park JW, Merchant ML, Teng Y, Zhang HG. miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics 2021; 11(9):4061-4077. doi:10.7150/thno.52558. https://www.thno.org/v11p4061.htm

CSE
Kumar A, Ren Y, Sundaram K, Mu J, Sriwastva MK, Dryden GW, Lei C, Zhang L, Yan J, Zhang X, Park JW, Merchant ML, Teng Y, Zhang HG. 2021. miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics. 11(9):4061-4077.

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