Interações imunoendócrinas entre leptina e céluls NK na obesidade

Abstract

Obesity is a chronic disease with a high global prevalence, affecting more than 700 million people worldwide and over 40 million in Brazil. Associated with profound metabolic alterations, excessive adiposity promotes the development of a state of chronic low-grade inflammation and sustained hyperleptinemia, conditions that contribute to the dysregulation of immune homeostasis. Natural Killer (NK) cells are particularly sensitive to metabolic signals, and obese individuals frequently exhibit impaired NK cell activity. In this study, we investigated, in vitro, how leptin modulates the frequency, activation, effector molecules, and intracellular signaling of NK cells from normal-weight (NP) and obese (OB) adults. To this end, cells were exposed to two concentrations of leptin, 10 nM and 50 nM, mimicking physiological and pathophysiological levels, respectively. Sex-stratified analyses were also conducted to evaluate potential effects related to sexual dimorphism. Obesity was found to reduce the frequency of circulating NK cells, particularly in women, along with decreased expression of the activating receptors CD16 and NKp46. Upon leptin exposure, NK cells from obese donors exhibited lower granzyme B intensity and reduced IFN-y production. Leptin further modulated these responses in an adiposity-dependent manner: whereas high leptin concentrations (50 nM) increased IFN-y production in NK cells from normal-weight individuals, an opposite response was observed in cells from obese individuals. Nevertheless, no differences were observed in CD107a and TNF-a levels following leptin treatment. At the level of intracellular signaling. NK cells from obese individuals showed reduced phosphorylation of ERK 1/2 and p38 after leptin treatment, correlating with impaired cytotoxic responses and IFN-y production, respectively. In contrast, mTOR phosphorylation was intrinsically reduced in NK cells from obese donors, regardless of leptin exposure. Regarding NF-kB, no differences were observed after treatment. Sex-stratified analyses revealed higher mTOR activation and greater granzyme B expression in NK cells from normal-weight men compared with normal-weight women at high leptin concentrations, whereas leptin-mediated suppression of IFN-y production was more pronounced in men, irrespective of body phenotype. No modulation was observed in other immunological parameters in the sex-based analyses. Taken together, these findings demonstrate that leptin exerts divergent effects on NK cells depending on the metabolic context and sex, contributing to the functional impairment observed in obesity.