Cutting Edge: Intestinal IL-17A Receptor Signaling Specifically Regulates High-Fat Diet-Mediated, Microbiota-Driven Metabolic Disorders

Abstract

Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial-specific (Il17ra ^ΔIEC ) and liver-specific (Il17ra^ΔLiver ) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17ra ^ΔIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA-driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet-mediated systemic glucose and lipid metabolism.

Figure 1.

Intestinal IL-17RA mediates systemic glucose and lipid metabolism. A) RT-PCR validating knockdown of Il17ra in the distal colon (n = 6 mice per group). B) Weight gain of Il17ra1^fl/fl (n = 10) and Il17ra^ΔIEC (n = 7) mice fed HFD for 16 wk. C) GTT of HFD-fed Il17ra^fl/fl (n = 8) and Il17ra^ΔIEC (n = 6) mice. D) Relative weight of eWAT after HFD. E) H&E staining of liver tissues from HFD-fed Il17ra^fl/fl (n = 8) and Il17ra^ΔIEC (n = 6) mice. F) ORO staining (left) and quantification (right) of liver tissues from HFD-fed Il17ra^fl/fl and Il17ra^ΔIEC mice. Data are obtained from at least two separate experiments. Error bars depict the mean ± SEM. *p < 0.05, Mann–Whitney U test and two-tailed, two-way ANOVA.

Figure 2.

IL-17RA signaling in the liver does not mediate systemic glucose metabolism or adiposity. A) RT-PCR validating knockdown of Il17ra in the liver (n = 4–5 mice per group). B) Weight gain of HFD-fed Il17ra1^fl/fl (n = 5) and Il17ra^ΔLiver (n = 4) mice. C) GTT of Il17ra1^fl/fl (n = 5) and Il17ra^ΔLiver (n = 4) mice fed HFD for 16 wk. D) Relative weight of eWAT after mice were fed HFD for 16 wk. E) Representative H&E staining of liver tissues from Il17ra1^fl/fl (n = 5) and Il17ra^ΔLiver (n = 4) mice fed HFD for 16 wk. All data are obtained from two separate experiments. Error bars depict the mean ± SEM. Mann–Whitney U test and two-tailed, two-way ANOVA.

Figure 3.

Intestinal IL-17A signaling effects systemic hormone and cytokine levels. A) Levels of serum c-peptide and insulin assessed via Luminex analysis. B) Levels of serum resistin and leptin assessed via Luminex analysis. C) Level of serum IL-22 assessed via Luminex analysis. All data are obtained from two separate experiments. Error bars depict the mean ± SEM. *p < 0.05, **p < 0.01, Mann Whitney U test.

Figure 4.

Intestinal IL-17RA signaling mediates microbiota-dependent changes in glucose metabolism. A) RT-PCR evaluation of fecal SFB levels before (day 0) and after (day 105) HFD treatment. B) Family-level 16S rRNA sequencing data collected from fecal samples. C) Weight gain of Il17ra^fl/fl (n = 2) and Il17ra^ΔIEC (n = 3) mice treated with an antibiotics mixture starting week 12 of HFD. D) GTT of Il17ra1^fl/fl (n = 2) and Il17ra^ΔIEC (n = 3) mice fed HFD for 16 wk and treated with an antibiotic mixture starting on week 12. E) Relative weight of eWAT after mice were fed HFD. F) H&E staining of liver tissues from HFD- and antibiotics-treated Il17ra^fl/fl (n = 2) and Il17ra^ΔIEC (n = 3) mice. G) ORO staining (left) and quantification (right) of liver tissues from HFD- and antibiotics-treated Il17ra^fl/fl (n = 2) and Il17ra^ΔIEC (n = 3) mice. Data from A and B are obtained from two separate experiments. For graph A, error bars depict the mean ± SEM. For graphs C, D, E, and G (right), error bars depict the mean ± SD. **p < 0.01, Mann Whitney U test and two-tailed, two-way ANOVA.