Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions

Abstract

Epidemiological studies have indicated that obesity is associated with a higher risk for certain cancers caused by elevated levels of adipocyte-derived hormones. Leptin, one such hormone produced by adipocytes, is a major regulator of metabolism and has also been shown to modulate immunity. However, its role in regulating human natural killer (NK) cell functions is largely unknown. Here, we show that the leptin receptor (Ob-R) is expressed on 5% of NK cells isolated from blood donors, as measured with flow cytometry, and expression of the signal-transducing long form of the leptin receptor Ob-Rb was confirmed with quantitative PCR. The Ob-R+ subpopulation displayed a lower expression of CD16, a cell surface receptor mediating antibody-dependent activation. Short-term stimulation with leptin increased IFNγ secretion, CD69 activation marker expression, and cytotoxic lysis of tumor cells; this was mediated by an improved conjugate forming between NK cells and tumor cells as well as higher expression of tumor necrosis factor-related apoptosis-inducing ligand. On the contrary, long-term incubation with leptin significantly impaired these NK cell immune functions and decreased cell proliferation. In addition, phosphorylation of Jak-2 after leptin stimulation was reduced in peripheral mononuclear blood cells from obese humans compared with normal-weight controls. NK cells represent an immune cell population that is crucial for an effective antitumor response. Here, we show that long-term exposure to leptin, similarly to the situation in obese individuals with elevated serum leptin levels, significantly impairs integral parts of NK cell immune functions, possibly linking leptin to increased cancer susceptibility in obesity.

Impact of the body mass index on perioperative immunological disturbances in patients with hip and knee arthroplasty

“…Interestingly, a study with a large cohort demonstrated that plasma leptin levels are stronger linked to a cardiovascular death in males than in females [26]. Furthermore, it could be shown that high-elevated leptin levels in obese individuals result in the development of a leptin resistance [10]. The data from this study demonstrate for the first time that numbers of peripheral CTLs and NK cells are decreased in pre-operative obese patients when compared to normal weight patients suffering from osteoarthritis.…”

“…In prior studies, it was demonstrated that long-term effects of the adipokine leptin led to immunomodulatory functions on various immune cells including NK cells [10]. Due to the fact that leptin expression correlates with the amount of adipose tissue [24], the immunomodulatory effects of long-term leptin incubation on immune effector cells could be an explanation for the reduced wound healing in overweight and obese patients.…”

“…Apart from its T-lymphocyte modulating role [6], it also inhibits the proliferation of monocytes and macrophages and enhances their cytokine secretion [7,8]. Our group could demonstrate that natural killer (NK) cells express the functional isoform of the leptin receptor (ObRb) [9] and a short-term stimulation of NK cells with leptin resulted in an increased interferon (IFN)-γ secretion and tumor cell lysis [10]. Obese individuals have highly elevated serum adipokine and cytokine levels-a so-called chronic low-grade inflammation.…”

“…Obese individuals have highly elevated serum adipokine and cytokine levels-a so-called chronic low-grade inflammation. Thus, a long-term incubation of NK cells with leptin (as seen in obese individuals) impairs the anti-tumoral NK cell functions [10], an interesting point, because obesity increases the risk for certain tumor diseases, like colorectal cancer, renal cancer, post-menopausal breast cancer, and prostate cancer [1]. The most highly expressed mRNA in adipocytes of normal weight individuals is the one of the anti-inflammatory adipokines, the adiponectin [11].…”

Weight control, endocrine hormones and cancer prevention

“…Furthermore, the role of adipocytes on malignance has been suggested via tumor-stroma interaction required during metastases or early micrometastases [13]. Recent data also suggest that adipocytes not only respond to hormonal signals, but also produce hormone-like factors such as pro-inflammatory leptin that may enhance oncological risk [14]. Although it is not clear how leptin interacts in IGF-1 mitogenic signaling, our previous studies conducted in TPA-promoted mouse skin cancer model have demonstrated that the reduction of both IGF-1 and leptin levels in response to weight loss corresponded to a concomitant inhibition of IGF-1-dependent mitogenic cascades and thus diminution of TPA-promoted signaling [5,6,15].…”