Resistance of Janus Kinase-2 Dependent Leptin Signaling in Natural Killer (NK) Cells: A Novel Mechanism of NK Cell Dysfunction in Diet-Induced Obesity

Abstract

Leptin acts not only as an anorexigenic hormone but also regulates cell-mediated immunity via leptin receptors (Ob-R) expressed on T and B lymphocytes. However, the impact of leptin on natural killer (NK) cells is currently elusive. We evaluated leptin effects on NK cells in relation to the body weight in rats using in vivo and in vitro approaches. Leptin was injected iv in male lean and diet-induced obese Lewis and F344 rats. NK cell numbers were analyzed in blood and spleen by fluorescence activated cell sorting and immunohistochemistry, and the activity of NK cells was measured by chromium release assay. Ob-R expression was investigated by confocal laser scanning and quantitative RT-PCR. To compare leptin-dependent intracellular signaling under basal and leptin- and tumor cell (MADB106)-stimulated conditions, intracellular target proteins of NK cells were evaluated by Western blotting. Number and distribution pattern of splenic NK cells were significantly different in lean and obese animals. Leptin administration resulted in a 4-fold higher stimulation of the NK activity in lean than obese animals. This was not due to a decreased expression of Ob-R because quantitative RT-PCR revealed significantly higher Ob-Rb mRNA levels in NK cells from obese rats. In contrast, postreceptor signaling is differentially abrogated in obese animals with significantly lower activation of postreceptor signaling components (Janus kinase-2p, protein kinase B pT308, AMPalphapT172) after an in vivo leptin challenge. In conclusion, the results for the first time assign leptin a central role as a modulator of NK cell number and activity only in lean but not obese subjects. The differential role of leptin has important implications for the influence of body weight in the response to systemic inflammations and in the immunological defense of cancer.

Inverse association of leptin levels with renal cell carcinoma: Results from a case-control study

“…[25][26][27] It has also been reported that the proinflammatory state of obesity may induce an attenuated response of immune competent cells to an acute endogenous or exogenous leptin challenge and inhibit the promigratory and activating effects of a leptin challenge on NK cells. 28 These reports along with the results of the present study support the hypothesis that obesity may lead to impaired immune functions and that low leptin levels among RCC patients suggest reduction or loss of leptin's anti-tumour effect (Figure 1). This study has several strengths including the exclusion of renal cancer cases with different underlying pathophysiology and the blinded evaluation in one batch of the serum analytes.…”

Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats

“…Additionally, the same positive effect was found for infection with pneumococcal pneumonia [21]. Comparing diet-induced obese (dio) with lean animals, Mito et al [22] showed a different cytokine response toward a leptin treatment in lean and dio mice and Nave et al [23] demonstrated a lack of intracellular signaling events in NK cells after leptin treatment in dio rats. Recent data additionally revealed a very distinct migratory performance, especially of B-and T-lymphocytes, in dio mice challenged by different chemokines [24].…”

Role of leptin in the pancreatic β-cell: effects and signaling pathways

“…Both proteins work as negative regulators of leptin-induced activation of the JAK/STAT pathway (Morris & Rui 2009). In addition to central leptin resistance, several studies on obesity models have observed attenuated leptin signaling in peripheral tissues (Prpic et al 2003, Lam et al 2006, Steinberg et al 2006, Nave et al 2008. In most cases, an increase in PTP1B or SOCS3 levels was associated with this attenuated response to leptin.…”