KYNA has been shown to regulate
KYNA has been shown to regulate iNKT cytokine release (Fallarini et al., 2010) and at high concentrations to reduce LPS-induced TNFα release from cultured peripheral blood mononuclear LP533401 hcl mg (Wang et al., 2006). Our results show that elevating KYNA to “exercised” levels is sufficient to promote an anti-inflammatory phenotype in adipose tissue with increased expression of anti-inflammatory cytokines involved in type 2 immune responses. In addition, we observed a decrease in the expression of inflammatory markers such as TNFα. Altogether, our data show a KYNA-induced increase in markers associated with Treg and ILC2 populations, both of which have been shown to regulate adipose tissue inflammation and insulin resistance (Brestoff and Artis, 2015, Lackey and Olefsky, 2016). The contribution of adipose tissue-resident immune cells to the browning phenotype, and to the regulation of energy homeostasis, has become the subject of active research (Kohlgruber et al., 2016). In this context, it is interesting that iNKT cells have been shown to be present in significant numbers in the lean adipose tissue and to be reduced in the obese state, and thus suggested to contribute to maintaining a state of low inflammation and insulin sensitivity (van Eijkeren et al., 2018). Among the proposed mediators of these effects are Il4, Il10, and Il13, which we observed to be induced by KYNA and with known anti-inflammatory properties. However, the contribution of Il4 for WAT browning and thermogenesis has been recently questioned (Fischer et al., 2017). Of note, KYNA also induced Il33 and ILC2 cellular markers, which have anti-inflammatory properties and promote adipose tissue beiging even in the absence of Il4 signaling (Brestoff et al., 2015).
Importantly, mice fed an HFD and treated daily with KYNA show reduced weight gain, improved glucose tolerance, and remarkably reduced circulating TG levels. This phenotype (also partially observed in chow-fed mice) was concomitant with an HFD-induced reduction in the expression of adipose tissue thermogenic genes, which was rescued by KYNA administration. Importantly, the effects of KYNA are lost in a Gpr35KO mouse model, which develops glucose intolerance and weight gain, and is more susceptible to the effects of HFD feeding. In addition, Gpr35KO mice show reduced browning of the subcutaneous adipose tissue induced by aerobic exercise. Interestingly, genome-wide association studies have previously linked Gpr35 with type 2 diabetes (Horikawa et al., 2000), although through unknown mechanisms. In human adipose tissue, GPR35 expression correlates with genes involved in transcriptional regulation of adipocyte browning, such as PRDM16 (Figures 7H and 7I). In sum, this work identifies a novel role for KYNA and Gpr35 in the regulation of energy metabolism that can potentially be explored therapeutically.
Acknowledgments We thank the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Gpr35tm1b(EUCOMM)hmgu), and INFRAFRONTIER/EMMA (https://www.infrafrontier.eu/). Funding information may be found at http://www.sanger.ac.uk/science/collaboration/mouse-resource-portal and associated primary phenotypic information at http://www.mousephenotype.org/. This work was supported by grants from Karolinska Institutet (J.L.R., P.-O.B., and P.B.), the Swedish Research Council (J.L.R., P.-O.B., and P.B.), the Novo Nordisk Foundation (J.L.R. and P.-O.B.), the Strategic Research Programs in Diabetes (J.L.R. and P.-O.B.) and in Regenerative Medicine (J.L.R.) at Karolinska Institutet, the Swedish Diabetes Association (J.L.R. and P.-O.B.), the European Research Council (P.-O.B., ERC-2013-AdG 338936-BetaImage; P.B. and Z.G.-H., aCROBAT ERC-St 639382), the Swedish Society for Medical Research (P.B.), the Family Knut and Alice Wallenberg Foundation (P.-O.B.), Skandia Insurance Company (P.-O.B.), Diabetes and Wellness Foundation (P.-O.B.), the Bert von Kantzow Foundation (P.-O.B.), the Stichting af Jochnick Foundation (P.-O.B.), and the Family Erling-Persson Foundation (P.-O.B.). J.L.R. was recipient of a Marie Curie Career Integration Grant, D.M.S.F. was supported in part by a postdoctoral fellowship from the Wenner-Gren Foundations (Sweden, CIG-294232), and J.C.C. is recipient of a postdoctoral fellowship from the Swedish Society for Medical Research (SSMF).