Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity

Abstract

Background/objectives Low-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. Methods We 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 antiinflammatory 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. Results We 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. Conclusions 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.

Pdgfrα-Cre mediated knockout of the aryl hydrocarbon receptor protects mice from high-fat diet induced obesity and hepatic steatosis

“…aeruginosa pigment molecule, pyocyanin, also an AHR activator, caused inhibition of adipogenesis resulting in wasting syndrome [ 73 ]. A recent study identified indigo, a naturally occurring AHR ligand, as having anti-inflammatory properties in visceral adipose tissue that effectively protected against HFD-induced glucose intolerance [ 74 ]. In another study it was shown that people and animals with metabolic syndrome had reduced levels of AHR agonist activity in fecal samples [ 75 ].…”

The Aryl Hydrocarbon Receptor (AhR) Mediates the Counter-Regulatory Effects of Pelargonidins in Models of Inflammation and Metabolic Dysfunctions

“…Because maintenance of intestinal homeostasis is increasingly recognized as an important therapeutic target in obesity and NASH, we then investigated whether Mt-P was beneficial in a rodent model of diet-induced NASH. NASH is a highly prevalent human disorder associated with metabolic syndrome and sub-clinical inflammation, for which therapy remains suboptimal [14,46,47,48,49]. Results shown in Figure 8, Figure 9 and Figure 10 and supplementary Figures S4–S6 demonstrate that treating mice with Mt-P at the dose of 5 mg/kg/day effectively protected from body weight gain, development of insulin resistance, and metabolic dysfunction caused by HFD-F.…”

Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases

“…In mice, supplementation of diet with AhR agonists or a Lactobacillus strain naturally producing AhR ligands improved metabolic impairments [ 67 ]. Furthermore, the AhR agonist indigo has been described to protect against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity [ 69 ]. Lin et al, suggest that the AhR ligand indigo has therapeutic potential to modulate inflammatory signals in obesity.…”

“…Lin et al, suggest that the AhR ligand indigo has therapeutic potential to modulate inflammatory signals in obesity. Moreover, AhR activation is known to decrease serum glucose and triglyceride concentrations, described highly increased in patients suffering from obesity and metabolic syndrome [ 69 ]. AhR deficiency has been linked with dyslipidemia and dysbalanced glucose homeostasis, two parameters known to contribute to the development of type 2 diabetes in humans [ 70 ].…”