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Theranostics 2022; 12(3):1388-1403. doi:10.7150/thno.62514 This issue Cite

Research Paper

Ginger nanoparticles mediated induction of Foxa2 prevents high-fat diet-induced insulin resistance

Anil Kumar^1*, Kumaran Sundaram¹, Yun Teng¹, Jingyao Mu¹, Mukesh K Sriwastva¹, Lifeng Zhang¹, Joshua L. Hood², Jun Yan¹, Xiang Zhang², Juw Won Park^3,4, Michael L Merchant⁵, Huang-Ge Zhang^1,6✉

1. James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202, USA.
2. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY40202, USA.
3. Department of Computer Engineering and Computer Science, University of Louisville, KY40202, USA.
4. KBRIN Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA.
5. Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA.
6. Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA.
*Present address: Division of Thoracic Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

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

Abstract

Rationale: The obesity epidemic has expanded globally, due in large part to the increased consumption of high-fat diets (HFD), and has increased the risk of major chronic diseases, including type 2 diabetes. Diet manipulation is the foundation of prevention and treatment of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance, however, remain to be identified. Here, we report that treatment with orally administered ginger-derived nanoparticles (GDNP) prevents insulin resistance by restoring homeostasis in gut epithelial Foxa2 mediated signaling in mice fed a high-fat diet (HFD).

Methods: Ginger-derived nanoparticles (GDNP) were added into drinking water to treat high-fat diet fed mice for at least one year or throughout their life span. A micro array profile of intestinal, liver and fat tissue of GDNP treated mice was used to analyze their gene expression profile. Genes associated with metabolism or insulin signaling were further quantified using the real time polymerase chain reaction (RT-PCR). Surface plasmon resonance (SPR) was used for determining the interaction between Foxa2 protein and phosphatic acid lipid nanoparticles.

Results: HFD-feeding inhibited the expression of Foxa2; the GDNPs increased the expression of Foxa2 and protected Foxa2 against Akt-1 mediated phosphorylation and subsequent inactivation of Foxa2. Increasing expression of Foxa2 leads to altering the composition of intestinal epithelial cell (IEC) exosomes of mice fed a HFD and prevents IEC exosome mediated insulin resistance. Collectively, oral administration of GDNP prevents insulin resistance in HFD mice. Interestingly, oral administration of GDNP also extended the life span of the mice and inhibited skin inflammation.

Conclusion: Our findings showed that GDNP treatment can prevent HFD-induced obesity and insulin resistance via protecting the Foxa2 from Akt-1 mediated phosphorylation. GDNP treatment provides an alternative approach based on diet manipulation for the development of therapeutic interventions for obesity.

Keywords: Ginger-derived nanoparticles, phosphatidic acid, Foxa2, insulin resistance, exosomes, skin inflammation, lifespan

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