Leptin modulates NK cell function and MAPK signaling in obesity

Obesity is characterized by chronic inflammation and sustained hyperleptinemia, conditions known to disrupt immune homeostasis. Natural killer (NK) cells are particularly sensitive to metabolic cues, and obese individuals frequently display impaired NK cell activity. Here, we investigated how leptin modulates NK cell frequency, activation, effector function, and intracellular signaling in normal-weight (NW) and obese (OB) adults. Obesity was associated with reduced frequencies of circulating NK cells, particularly among women, along with decreased expression of the activating receptors CD16 and NKp46. Upon leptin exposure, NK cells from obese donors exhibited impaired effector function, characterized by reduced granzyme B intensity and diminished IFN-γ production. Leptin further modulated these responses in a weight-dependent manner: whereas high-concentration leptin (50 nM) enhanced IFN-γ production in NK cells from normal-weight individuals, it induced a suppressive response in cells from obese donors. At the signaling level, NK cells from obese individuals showed reduced phosphorylation of ERK1/2 and p38 following leptin stimulation, which correlated with impaired cytotoxic and cytokine responses. In contrast, mTOR phosphorylation was intrinsically reduced in NK cells from obese donors, independent of leptin exposure. Sex-stratified analyses revealed higher mTOR activation and granzyme B expression in NK cells from lean men compared to lean women under high leptin conditions, whereas leptin-mediated suppression of IFN-γ was more pronounced in men across both NW and OB groups. Together, these findings suggest that leptin exerts divergent effects on NK cells depending on metabolic and sex-related context, contributing to the functional impairment observed in obesity.