Abstract
Background/objectivesLow-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts.MethodsWe screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation.ResultsWe identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT.ConclusionsIndigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.
Highlights
These authors contributed : Yi-Hsuan Lin, Helen LuckThese co-senior authors contributed : Shawn Winer, Daniel A
The output of the screening consisted of cytokine readouts known to modulate insulin resistance (IR), including TNFα and IL-10
The 20 plantderived or crude extracts in this screen consisting of indigo, aliso B acetate, gentiopicroside, peimine, perillaldehyde, phellodendrine, wedelolactone, bergapten, picroside I, baicalein, baicalin, wogonin, wogonoside, berberine, cinnamaldehyde, Ephedra sinica, ephedrine, psynephrine, 6-shogaol, and 6-gingerol were tested in three different doses according to available literature and compared to the vehicle in the production of these cytokines by visceral adipose tissue (VAT) stromal vascular cell (SVC) of mice fed 14 weeks of high-fat diet (HFD)
Summary
Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation
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