Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence.

Obesity is associated with an increased colon cancer incidence, but underlying mechanisms remained unclear. Previous studies showed altered Natural killer (NK) cell functions in obese individuals. Therefore, we studied the impact of an impaired NK cell functionality on the increased colon cancer risk in obesity. In vitro investigations demonstrated a decreased IFN-γ secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with the adipokine leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In animal studies, colon cancer growth was induced by injection of azoxymethane (AOM) in normal weight and diet-induced obese rats. Body weight and visceral fat mass were increased in obese animals compared to normal weight rats. AOM-treated obese rats showed an increased quantity, size, and weight of colon tumors compared to the normal weight tumor group. Immunohistochemical analyses demonstrated a decreased number of NK cells in spleen and liver in obesity. Additionally, the expression levels of activating NK cell receptors were lower in spleen and liver of obese rats. The results show for the first time that the decreased number and impaired NK cell function may be one cause for the higher colon cancer risk in obesity.

Decreased NK cell functions in obesity can be reactivated by fat mass reduction.

OBJECTIVE: Natural killer (NK) cells are the first defense against malignant cells, and their functions are severely impaired in individuals with obesity. However, it is not known whether functions can be re-activated after weight loss. The alterations of NK cell functions after fat mass reduction were investigated. METHODS: Thirty-two healthy adults with obesity were divided into control and experimental groups. Participants of the experimental group performed a 3-month program of exercise training and nutrition. Anthropometric, physiological, and metabolic parameters and plasma adipocytokines were determined. Peripheral blood mononuclear cells were analyzed by means of flow cytometry and Western blot assay for various NK cell-specific functional parameters and leptin signaling components. NK cell-mediated cytotoxicity assay with leptin stimulation was performed. RESULTS: Male participants significantly decreased their body fat mass (P < 0.05) and increased physical fitness (P < 0.05). Plasma leptin levels were significantly reduced (P < 0.05) and intracellular interferon gamma (IFN-γ) expression in CD56(dim) NK cells was significantly increased (P < 0.001) 3 months after study end. Stimulation of NK-92 cells with different leptin dosages revealed a significant dose-dependent decrease of specific tumor cell lysis. CONCLUSIONS: The present study demonstrates a reactivation of NK cell functionality after body fat mass reduction in persons with obesity.