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 (Il17raΔIEC) and liver-specific (Il17raΔLiver) 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. Il17raΔIEC 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.

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

“…Mice were treated with antibiotics using methods similar to those previously described 55 . Briefly, drinking water was substituted with an antibiotics cocktail containing vancomycin (0.5 g/L), ampicillin (0.5 g/L), neomycin (1 g/L), and metronidazole (1 g/L) on week 12 of HFD.…”

“…ORO tissue staining was performed as previously described 55 . Briefly, liver tissues were harvested and frozen in an OCT compound medium (Sakura).…”

Interleukin-17 Family Cytokines in Metabolic Disorders and Cancer

“…Another way in which the IL-17 cytokine family may link metabolic dysregulation with cancer is through its impact on intestinal microbiota [ 263 , 264 ]. Th17 cells in the small intestine have been found to promote the expansion of gut microbiota associated with leanness and metabolic homeostasis in an IL-17-dependent manner [ 263 ].…”

“…Similarly, in patients with MetS, serum levels of IL-17 are reduced in conjunction with the increasing presence of metabolic abnormalities [ 265 ]. IL-17 signaling to intestinal epithelial cells drives changes in the microbiota, and this mechanism is required for the resistance to metabolic disorders induced by a HFD [ 264 ]. This intestinal-specific IL-17–microbiota–metabolism axis is of special interest because it differs from the traditional view of obesity as a proinflammatory state, where researchers found increased levels of IL-17A in the serum [ 266 , 267 ] and visceral adipose tissues [ 268 ].…”