Abstract
Overweight and obesity are major public health challenges worldwide. Obesity is associated with a higher risk for the development of several cancer types, but specific mechanisms underlying the link of obesity and cancer are still unclear. Natural killer (NK) cells are circulating lymphoid cells promoting the elimination of virus-infected and tumor cells. Previous investigations demonstrated conflicting results concerning the influence of obesity on functional NK cell parameters in small animal models. The aim of the present study was to clarify potential obesity-associated alterations of murine NK cells in vivo, implementing different feeding regimes. Therefore, C57BL/6 mice were fed a normal-fat diet (NFD) or high-fat diet (HFD) under restrictive and ad libitum feeding regimes. Results showed diet and feeding-regime dependent differences in body weight, visceral fat mass and plasma cytokine concentrations. Flow cytometry analyses demonstrated significant changes in total cell counts as well as frequencies of immune cell populations in peripheral blood comparing mice fed NFD or HFD in an ad libitum or restrictive manner. Mice fed the HFD showed significantly decreased frequencies of total NK cells and the mature CD11b+CD27+ NK cell subset compared to mice fed the NFD. Feeding HFD resulted in significant changes in the expression of the maturation markers KLRG1 and CD127 in NK cells. Furthermore, real-time PCR analyses of NK-cell related functional parameters in adipose tissue revealed significant diet and feeding-regime dependent differences. Most notable, real-time cytotoxicity assays demonstrated an impaired cytolytic activity of splenic NK cells toward murine colon cancer cells in HFD-fed mice compared to NFD-fed mice. In conclusion, our data demonstrate that feeding a high-fat diet influences the frequency, phenotype and function of NK cells in C57BL/6 mice. Interestingly, restricted feeding of HFD compared to ad libitum feeding resulted in a partial prevention of the obesity-associated alterations on immune cells and especially on NK cells, nicely fitting with the current concept of an advantage for interval fasting for improved health.
Highlights
Obesity is a complex public health problem affecting all age and socio-economic groups worldwide
The daily food intake of mice fed the high-fat diet (HFD) ad libitum or restrictive was significantly lower compared to the corresponding normal-fat diet (NFD)-fed groups, the energy intake was higher in HFD-fed mice compared to NFDfed mice in both feeding regimes due to the high energy content of the HFD (Supplementary Table 3)
Mice fed a HFD ad libitum or restrictive had a significantly increased daily intake of fat and protein and a significantly decreased daily intake of carbohydrates compared to the corresponding NFD control groups (Supplementary Table 3)
Summary
Obesity is a complex public health problem affecting all age and socio-economic groups worldwide. Overweight and obesity are main risk factors for the development of several diseases, like diabetes, coronary heart disease, as well as kidney and musculoskeletal disorders [2,3,4,5]. Obese individuals have an increased susceptibility to infections and a higher risk for numerous cancer types, like postmenopausal breast, colorectal, kidney, esophageal and pancreatic cancer [6,7,8]. The role of obesity in cancer development is not completely understood, several biological mechanisms for the association between excess body weight and cancer, like hyperinsulinemia, increased levels of sex hormones, alterations in microenvironment or dietary factors have been discussed [10]. Animal and human studies described an impaired NK cell physiology in obesity [15,16,17,18,19,20,21]
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