A new Cutting Edge article, in the April 2013 issue of the Journal of Immunology, identifies a link between leptin and T helper (Th)17 cells, based on the evidence that leptin was able to promote Th17 responses in human CD4+ T cells and in mice, both in vitro and in vivo, by inducing the transcription of the Th17 master regulator RORγt.
In 1994 Zhang et al. identified leptin as the product of the obese (ob) gene, and this factor was coined leptin the following year, derived from the Greek word leptos, meaning thin. Leptin is a hormone predominantly made by adipose cells and enterocytes in the small intestine, which controls energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes.
This hormone is a potent immune regulator through induction of TNF-α, IL-6 and IL-12 production, and an inhibitior of CD4+CD25+FOXP3+ regulatory T cells.
In this study, Yiyun Yu and colleagues from the Department of Medicine, University of California Los Angeles, Los Angeles, CA, found that in the presence of increasing concentrations of leptin, Th17 cell numbers increased in a dose-dependent manner in cultures of healthy human PBMC. Importantly, the researchers observed that leptin promoted Th17 differentiation by inducing RORγt (ROR nuclear hormone receptor family) transcription in CD4+ T cells.
The hormone also increased Th17 responses in (NZB × NZW)F1 lupus-prone mice, while the authors also report a positive correlation between plasma leptin and IL-17 in systemic lupus erythematosus (SLE) patients.
This study, along with previous research implicating leptin’s Th17-promoting effects in collagen-induced arthritis and Hashimoto’s thyroiditis, validates the link between adipokines, metabolism/nutrition and susceptibility to autoimmunity.
A 2015 study, found that the leptin receptor (lepR) deficiency in CD4+ T cells resulted in a selective defect in both autoimmune and protective Th17 responses. In mice with T cell-specific ablation of lepR, the authors described an impaired STAT3 phosphorylation, RORγt expression and IL-17/IL-22 secretion in vitro and in vivo, suggesting that lepR plays a broad role in STAT3-dependent T cell differentiation. For instance, it might influence the downstream signaling of IL-23R, which is also STAT3 dependent.
A 2020 study indicates that a high concentration of the hormone promoted the differentiation of Th17 cells from MRL/lpr lupus mice by activating the NLRP3 inflammasome. The authors report that leptin pushed up the expression of IL-17A, IL-17F, NLRP3, and IL-1β and increased the number of Th17 cells in lupus mice.
This study concluded that the hormone promoted the differentiation of Th17 cells from MRL/lpr lupus mice, via activating the NLRP3 inflammasome.
As per 2021 review leptin signaling promotes transcription of RAR-related orphan receptor gamma (RORγt), which is the critical transcription factor for Th17 fate. The authors of this review discuss that obesity is associated with a chronic, low-grade systemic inflammation that has been shown to promote the development of type 2 diabetes, autoimmunity, nonalcoholic fatty liver disease, asthma, and cardiovascular disease.
Thus, now it is clear that the hormone plays a critical role in obesity-associated inflammation by promoting pro-inflammatory immune phenotypes. While this hormone has not been successful in treating obesity as a weight loss drug, it is possible that targeting leptin or leptin signaling could be therapeutic for autoimmune disease or the low-grade, chronic inflammation associated with obesity and metabolic syndrome.
A 2022 study reports an association between obesity and expansion of hybrid Th2/Th17 and Th17-like cells rather than classic Th2-like cells.
Elevated leptinemia is known to aggravates allergic diseases. In this study, higher plasma leptin levels were quantified in moderate and severe allergic asthma patients when compared with the control group. This phenomenon should be associated with the ability of cytokines related to Th17 (IL-1β, IL-6 and IL-17) and Th2 (IL-4 and IL-5) cells in up-regulating the production of this adipokine.
The authors concluded that obesity might increase allergic asthma severity by favoring the expansion of Th17-like and Th2/Th17 cells and decreasing regulatory CD4+T cell subsets, being adverse effects probably mediated by leptin overproduction.