Beta Fulltext view is in preview — article structure may vary. Browse all articles
Contents
Open Access Journal of Endocrinology Research Article 28 min read

Alteration in Natural Killer (NK) cell Function in Obesity-correlating with comorbidities development like cancer and type 2 diabetes-A Minireview

Kulvinder Kochar Kaur*, Allahbadia G and Mandeep Singh
* Corresponding author
ISSN: 2578-4641  10.23880/oaje-16000140  Received: August 12, 2019  Published: August 26, 2019
 — views
 74 references
 3 figures
PDF
Keywords
Natural Killer Cells Obesity Cancer Adipose Tissue
Abstract

Recently obesity has become a worldwide epidemic, with over 600 million adults worldwide being obese of which 10.8% are males and 14.9% females. Now obesity has overtaken undernourishment for the first time and is increasing by leaps and bounds. Hence marked efforts are being done to understand the aetiopathogenesis. In our earlier reviews we have tried to understand the aetiopathogenesis involving different aspects like inflammation in general in obesity, hypothalamic inflammation, GIT inflammation, and others which have influenced development of medical treatments having edge over bariatric surgery but have not been successful in getting any stable medical therapy that can be used for long. Natural Killer (NK) cells represent one of the populations of the lymphocytes belonging to the innate immune system. By definition they are the cells that have the capacity to kill infected or transformed cells without needing any previous activation. Besides their cytotoxic capacity, they can also produce inflammatory cytokines like interferon gamma (IFNγ) and thus are a key part of early immune responses. In view of these abilities which make them stand out, these NKcells are very important parts for host protection, mainly antitumor and antiviral immunity. In the last 10years, a lot of work has been done to study the effect of obesity on NKcell biology, giving a full briefing of systemic dysregulstion of NKcell functions. Recently various publications have examined the role of NKcells in the homeostasis of adipose tissue (AT) and the aetiopathogenesis of obesity. Here we review studies pertaining to the role of how NKcells are involved in obesity.

Introduction

In the last century obesity has surfaced as the biggest global health problem in view of both ,the changes in environment along with changes in society where positive energy balance and thus weight gain has resulted, main changes being consumption of high calorie foods /high fat foods, associated with inadequate physical activity, moving towards sedentary lifestyle [1]. As a result obesity prevalence practically doubled since 1980 all over the world, with world health organization (WHO) showing that greater than 39%of adults greater than /equal to 18year were overweight of which 13% were obese [2]. Additionally minimum of 41million children below 5yrs were overweight or obese. Importantly severe obesity, a body mass index (BMI) greater than 35kg/m2 is becoming a part of this global epidemic, and that has severe bad effects on health, with increase in BMI implying increased mortality risk just like low BMI does [3, 4, 5]. However now overweight or obese have become bigger killers in contrast to malnourished or underweight. As per WHO overweight and obesity are the causative factors for 44% of type 2 diabetes mellitus (T2DM), result in 23% of ischemic heart disease patients and roughly 7-41% of some cancers. Of these greatest association is of T2DM with obesity, with obesity related T2DM expected to double to 300 million by the year 2025 [6]. We reviewed the importance of treating both obesity and diabetes together in view of that [7]. To further understand the aetipathogenesis we decided to review a role of Natural Killer cells in obesity in this review.

Methods

Thus we used the PubMed search engine to find articles using MeSH terms like ‘’NK cells’’ ‘’obesity‘’, ’’cancer’’, ’’inflammation” and obesity’’.

Results

We found a total of 356 articles out of which we selected 73articles for this review. No meta-analysis was done.

Cancer and Obesity

Worldwide, cancer has become a leading cause of mortality, with 7.6 million deaths occurring yearly [8]. A report from centre of diseases control (CDC) in United States have pointed to obesity being responsible for 40% of cases of cancer, that accounts for 630,000 diagnosis in 2014 alone [9]. This study is similar to what has been found all over the world [10]. Multifactorial changes like hormones, cytokines and immunity observed in cancers related to obesity. Obesity is related to increased insulin levels that further promotes the development of some obesity related cancers like colorectal, pancreatic, liver and endometrial [11, 12, 13]. Various studies have also picked up links with leptin, an adipokine levels that are raised in obese children and adults and cancer. Most researchers trying to study leptin in relation to obesity have mainly concentrated on breast cancer, in which case leptin has the ability to directly stimulate breast cancer cells proliferation [14]. Also the other part common to obesity related cancer occurring is the chronic inflammation present in obesity [15]. Various studies have emphasized on the interaction between inflammation and cancer developing as exemplified by colonic carcinogenesis in pts suffering from inflammatory bowel disease [16].

Obesity and Immune Regulation Disorder

Systemic inflammation development is driven by obesity that besides being behind the formation of malignancies, leads to other morbidities like development of T2DM and cardiovascular disease (CVD). Various cytokines that are increased in obese subjects have been demonstrated to interfere with normal homeostasis processes, like interleukin 1 (IL1) and insulin signaling or IL-17 and adipogenesis [17, 18]. Inflammation that has been stimulated with Obesity has been demonstrated to stimulate the liver carcinoma development [19]. This chronic inflammation originates initially through a dysregulated immune system. Changes in a subset of immune system, associated with a loss of control and rise in inflammatory profile has been found by many researchers [20, 21, 22, 23]. This altered immune system besides occurring in adults having established comorbidities, is also seen in obese children even as old as 6 years of age, much before the overt disease come in the scene [24].

This supports this hypothesis that obesity is the one that stimulates chronic inflammation that comes before comorbid diseases that includes cancer origin. In addition to the raised inflammatory burden, there is a negative effect of obesity on the bodies tumor effector populations, like natural killer cells (NK) cells.

Natural killer cells (NK) cells

NK cells constitute a subset of innate lymphocytes, that have a very important role in early host protection [25]. Difference from classical T and B lymphocyte is that NK cells can respond to infected or transformed cells at a fast pace, not needing any activation, through their manufacture of lytic molecules like perforins or granzymes [26]. NK cells might also modulate the consequent immune responses via their production of cytokines immediately like IFNγ, TNFα, IL-6, and granulocyte-macrophage colony-stimulating factor (GM- CSF). NK cells activation is controlled tightly via the germline coded receptors expression, that in response to environmental cues can change the interrelation of activating and inhibitory signals remaining in balance, that =>activation of the cells. If self-identifying molecules like human leukocyte antigen (HLA) are lost that normally give an inhibitory signal, through killer cell immunoglobulin like receptors (KIRs) will=>activation of NK cells, and the lysis of the target cells. Further NK cells also get activated by binding of activation molecules like NKG2D that get up regulated by stressed and transformed cells [27]. Cancer stem cells (CSC) can be targeted by NK cells too, that can seed metastasis and promote tumor bulk [28]. Besides being activated in response to malignant cells or CSC, NK cells might also get activated through soluble cytokines that includeIL-2, IL-12, IL-15, and IL-18. A critical component of NK cells activation that has been emphasized is immunometabolism, at rest NK cells metabolize glucose through glycolysis coupled to oxidative phosphorylation with great levels of energy getting released. On activation, NK cells immediately increase their rates of aerobic glycolytic metabolism that fuels biosynthetic precursors for cytokine and lytic granule synthesis for NK cells effector function has been shown by inhibition of glycolysis with the use of 2-deoxy glucose (2DG), that inhibition of NK cells cytokine production along with lytic molecule synthesis [29, 30, 31]. Mammalian target of rapamycin (mTOR) is a master regulator of NK cells metabolism. The requirements have been shown to be indispensable for NK cells effector function. Initially it was considered that NK cells don’t have any memory, but various researchers have demonstrated that murine NK cells can form memory [32]. Similarly workers showed that human NK cells have been demonstrated to learn during training, where an early cytokine stimulation => a boosted response various days or weeks later [33, 34]. A new therapeutic avenue has been released with usage of trained NK cells as a potent immunotherapy.

NK Cells in Cancer

NK Cells are extremely important part of antitumor immunity, since they are rich in potent antitumor machinery that includes cytotoxic granules, proinflammatory cytokines and death –inducing ligands like FAS ligand and TNF related apoptosis inducing ligand (TRAIL). For protection from cancer gets supported by the increased prevalence of cancer in humans with defective NK cells like in Chediak-Higashi disease, and validated by the exacerbation of cancer in NK cell deficient mouse models [35]. Association between low NK cell activity and cancer risks have also been emphasized by some studies. In a study that extended for 11years, a longitudinal study showed that subjects with low NK Cells activity levels were at a >risk of developing cancer that emphasizes on how essential NK Cells are in the prevention of overt malignancy and immunosurvellace [36]. Further in 872 patients cohort, cases with low NK Cells activated (IFNγ production) had a 10 fold >risk of colorectal cancer as compared to those with high NK Cells activity [37]. On the other hand, in a colorectar cancer cohort patients and matched controls, expression of high NK cell activity haplotype of NKG2D, HNK1, was correlated with decrease in risk of colorectal cancer. Besides the cancer risk NK Cells have an important role in predicting the prognosis of patients developing cancer [38]. 50 patients with primary squamous cell lung carcinoma, high NK cell infiltration into the tumor was associated with a good outcome. Besides cancer can also induce defects in NK cell, using a KRAS mutation model of pancreatic cancer, Kaur, et al. demonstrated the defect in NK cell frequencies and functions during the preneoplastic stages of pancreatic cancer, suggesting that cancer induces early defects in NK cell that allow the progression and expansion of the disease. In that v study diet induced obesity (DIO), compounded the change of NK cell in the tumor microenvironment that helped in the expansion of pancreatic tumors [39]. Those who studied the NK cell functions in cases of acute myeloid leukaemia (AML) also demonstrated that NK cells were dysfunctional with decreased cytokine production and degranulation. Incubation of NK cells that were obtained from healthy donors with AML blasts induced similar defects suggesting that the defects that were communicated were indiced by cancer [40]. Mamassier, et al. gave an exhaustive explanation on this concept by demonstrating that human breast cancer cells could promote tolerance in NK cells by decreasing the expression of activating receptors like NKG2D, and those tumor derived factors like transforming growth factor beta (TGFβ), directly decreased NK cell activity [41]. In view of their high effector functions, NK cell become an attractive target for cancer immunotherapy. Various methods have been demonstrated, which vary from adoptive transfer of NK cells into patients, cytokine therapy or targeting /modifying NK cells receptors to enhance their cancer killing function [42]. Adoptive transfer of NK cells means isolation of either autologous or allogenic cells that was followed by their expansion and activation before transfusing them to the patients [43, 44, 45, 46]. Clinically important responses have not been shown from studies that were investigating autologous transfer. More positive effects were documented with allogenic approach, mainly with KIR mismatch in those subjects presenting with haemoatological cancers like AML Use of Adoptive transfer of allogenic, NK cells in 2010, Rubnitz et al. presented astounding data in childhood AML, demonstrating 100%remission rates [47]. Transferring cytokine trained NK cells is other method that holds promise, involves harnessing the training of memory potential of NK cells. NK cells separated whether autologous or allogenic get activated in vitro with the use of a mixture of cytokines (IL-2,IL-15,and IL-18)and following restimulation, demonstrated enhanced effector responses. Cytokine trained NK cells showed increased effector functions in a phase-I clinical trial and a clinical response in 5/9 patients with 4 total remissions [48]. Together these studies project a key role for NK cells in tumor immunity and their potential therapeutic responses.

Obesity and NK cells

Lynch et al reported in 2009 that NK cells were changed in a cohort of morbidly obese patients [49]. A reduction in NK cells frequencies were reported in obese as compared to lean ones along changes in the surface repertoire of NK cells activating and inhibitory molecules. NK cell cytotoxic abilities were decreased in the same group of patients with NK cells that were isolated from obese patients killing much less of the K562 myeloid leukaemia cells compared to healthy controls. Variety of other publications also emphasized on the negative effect of obesity on NK cells [22, 50, 51, 52]. Viet, et al. in 2017 demonstrated raised expression of activation markers like CD69 on NK cells from obese patients in parallel with a loss of function as measured by degranulation and the synthesis of macrophage inflammatory protein (MIP)-1β or IFNγ. The resident NK cells in tissues also get influenced by obesity, as shown by Shoae-Hasseini et al. in 2017, that NK cells resident in AT of obese subjects had low expression of NKp30 and NK p44 as compared to lean controls. Thus for finding when these defects get established, NK cell frequencies and functions of a cohort of obese children between 6-16yrs of age, free of overt metabolic diseases, did show greater evidence of IR. Tobin et al. suggested that defective tumor lysis by NK cells isolated from obese children, was possibly due to disturbed synthesis of granzymes B and perforins. This pointed that NK cells defects get seeded very early in obesity much prior to the development of overt metabolic diseases .A good thing was that the impact of weight loss after bariatric surgery was shown to cause normalization of these NK cell cytotoxicity six mths after surgery as shown by Moulin, et al. [53]. Thus pointing that once weight loss achieved, defects in NK cells induced by obesity could be reversed. Further this was proved by 2 researchers, 1st being by Jahn et al. who demonstrated that weight loss in obese subjects with the use of diet along with exercise =>increased IFNγ synthesis by NK cells [54]. Barra, et al. in the 2nd one demonstrated that high intensity interval training (HIIT) raised NK cells frequencies and function in obese women along with mice, besides obesity, breast cancer cells were injected intravenously into the mice and it was shown that HIIT decreased tumor burden, with a hypothesis by the authors that this got mediated through increase in NK cells activity (Figure 1) [55]. Right now how HIIT restores NK cells functions is not clear.

How obesity causes defects in NK cells have gradually started to be understood, with various studies demonstrating that leptin and adipokine levels are increased proportional to the AT mass, hence are increased in obese adults as well as children, might influence NK cell functions. Leptin is a peptide hormone that is synthesized by adipose tissue mass, hence are mainly acting as a safety signal [56, 57] normally physiologically, is increased in obese adults and children [24, 58]. Besides regulating energy expenditure leptin has been found to be an essential controller of Immune system [59, 60]. NK cell frequencies were decreased in the periphery, liver and spleen in leptin receptor deficient (db/db) mice, that points to the importance of leptin in regulating NK cells development [61]. Additionally activation of NK cells was also impaired in leptin receptor deficient mice. Nave, et al. confirmed the importance of leptin in regulating NK cells and gave a mechanism via which resistance of leptin signaling in NK cells was the important factor in their dysfunction in murine models of obesity [62]. Leptin resistance has been known to be an important part of obesity that has more roles than simply regulating NK cells and with the classical actions of leptin in energy homeostasis [63]. Laue, et al. found that the leptin receptor expression was higher on NK cells from obese subjects as compared to healthy controls; but authors found decreased downstream signaling in obese donors. Leptin stimulation caused a rise in cytokine production (IFNγ) IN NK cells from healthy donors but not obese donors, in same study, though proliferation levels were not the same [64].

Figure 1: NK Cells in Obesity [74].
Click to enlarge
Figure 1: NK Cells in Obesity [74].

genes that were involved in lipid handling and metabolism. On further exploration they found that culture of NK cells with free fatty acids (FFA) oleate and palmitate, recapitulated obesity like defects in NK cells, with loss of tumor lysis, blunted cytokine production and a failure of metabolic programming. With the use of murine models of malignancy, they demonstrated decreased antitumor immunity with FFA treated NK cells, emphasizing a direct link between obesity induced NK cell defects and cancer (Figure 2).

Figure 2: NK Cells [74].
Click to enlarge
Figure 2: NK Cells [74].

Adipose Tissue and NK cells

Besides their role in host protection, NK cells influence tissue homeostasis, at sites that include uterus and adipose depots. As seen by Perdu, et al. showing that maternal obesity defective NK cells in the uterus, with decreased numbers along with hyper responsiveness resulting in increased expression of décor in that can limit trophoblast survival altered placental development. How essential NK cells are for adipose tissue homeostasis and initiating IR has been demonstrated in various studies [24, 67, 68, 69].

O’Rourke et al working on NK cells in human AT, showed an increased activation profile in AT as compared to NK cell from the blood, and in a future study, they gave proof for the 1st time that NK cells could regulate AT macrophages, pointing to a positive role in the development of IR. Systemic NK cell ablation reduced accumulation of macrophages in the AT and modest improvement in insulin sensitivity [70, 71]. Wensveen, et al. showed how NK cells were important in monitoring AT stress through the expression of natural cytotoxicity receptors (NCRs). On recognition of NCR’s, while expression was up regulated on stressed adipocytes in HFD fed animals, NK cells were demonstrated to produce IFNγ, that promoted recruitment of macrophages into AT. These macrophages infiltrating initially had the task of phagocytosing apoptotic adipocytes, also synthesized high levels of inflammatory cytokineIL-1β. In IR role of IL-1 has been implicated, besides in the pathogenesis of T2DM. This role of NK cells in pathogenesis of IR was substantiated by further studies from Lees’s laboratory, who demonstrated that HFD increased NK cells numbers along with synthesis of pro-inflammatory cytokine TNFα, in epididymal, not subcutaneous, AT. On depletion of NK cells, an improvement was seen in obesity induced IR in parallel with reduction in both AT macrophages and inflammation. On the other hand expansion of NK cells after IL-15 administration or reconstitution of NK cells into NK cell deficient mice increased both AT macrophage infiltration and inflammation exacerbated IR. Theirich, et al. elaborated on specific subsets of NK cells that expressed IL-6Ra and colony stimulating factor 1 receptor (CSFR1) that were expanded in obese mice and humans and described their contribution to IR. Ablating CSFER1 expressing NK cells abrogated the development of obesity and IR, giving more proof for a homeostatic role for NK cells in metabolism.

O’Sullivan, et al. further elaborated on a role of AT resident innate lymphoid cells (ILC), specifically ILC1, in the development of IR. Although NK cells belong to ILC 1 Lineage, these authors demonstrated that ILC1 in the AT were phenotypically different from classical NK cells. Agreeing with this Boulenoaur, et al. demonstrated that under steady state conditions, IL1C’s are enriched in AT from both mice and humans, and these cells show an AT specific phenotype. Further they demonstrated that these ILC’s can regulate AT macrophage through their capability to kill inflammatory macrophages. AT macrophages express the NKG2D ligand, Rac1 that makes them a target for NK cell lysis. On initiation of HFD feeding NK cells lost their capacity to kill macrophages and increased synthesis of IFNγ that promoted the recruitment of inflammatory macrophages promoting obesity associated metabolic defects. Further Sasaki, et al. showed mice lacking ILC2 or ILC3 cells but not NK cells are resistant to obesity. Adoptive transfer of naïve ILC2’s isolated from small intestine (SI) but not from white AT restores the induction of DIO in Il2rg-/- Rag 2-/- mice. Analysis of transcriptional differences showed that SI-ILC’s express higher levels of IL-2 than do WAT-ILC2s and that blockade of IL-2 signaling impairs weight gain and reduces the populations of ILC2 and ILC3 in the SI, Suggesting a role of the IL-2/ILC3/3axis in the induction of obesity [72]. Further Rakshandehroo, et al. tried to explain how over production and /or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lesd to IR. The physiological functions of glucosylceramides being, they are presented by APC as endogenous lipid antigens via CD1 to activate a unique lymphocyte species, the CS-1d restricted invariant (i) Natural killer T (NKT). Recently adipocytes have emerged as lipid APC, which can activate AT-resident iNKT cells and thus contribute to whole body energy homeostasis. Thus they investigated a role of glucosylceramides biosynthesis pathways, in the activation of iNKT cells by adipocytes. UDP-glucose ceramide glucosyltransferase (Ugcg), the 1st rate limiting step in glucosylceramide biosynthesis pathway, was inhibited through chemical compounds and shRNA knockdown. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFNγ and IL4 secretion). Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore decreased expression level of either B4Galt5or 6 indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme resulted in increases iNKT cell activation. In addition, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in AT; Inhibition of endogenous glucosylceramide production results in reduced iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes (Figure 3) [73]. In total these researches give enough proof that NK cells are involved in the initiation of the macrophage-driven inflammatory phenotype reported in obese AT.

Figure 3: Adipocytes in NK cells [73].
Click to enlarge
Figure 3: Adipocytes in NK cells [73].

Conclusion and Future Directions

With obesity becoming a worldwide epidemic and its associated comorbidities like T2DM, CVD and many cancers need is there to find a solution, NK cells are essential frontline effectors cells in protecting the host that includes surveillance of tumor surveillance and clearance. NK cell immunotherapy looks to be a good strategy for the therapy of cancer, especially blood based cancers. A negative effect of obesity right from childhood into adulthood occurs on NK cell function has been presented in this review. It seems that the obese microenvironment drives defects in NK cell metabolism that causes functional failures. Hence doubt might be there regarding NK cell therapies will be able to be of help in obese mainly acting as a safety signal [56] patients. More work in murine models of obesity and obese patients will be required to get a certain answer. Besides their role in protecting host, NK cells have important role in maintenance of tissues like AT. NK cells and ILC1 also directly control macrophages, but on HFD feeding NK cells lose their capacity along with changing their control of AT. This activation along with accumulation of inflammatory macrophages which drive IR-a crucial player in driving DM and cancer. If targeting this NK- Macrophage interaction will become a possible way to treat IR and tumorigenesis still remains a query.

References

  1. Yumuk Y, Tsigos C, Fried M, Schindler K, Busetto L, et al. (2015) Obesity management task force in the European Association for the Study of Obesity: European guidelines for obesity management in adults. Obes Facts 8(6): 402-424.
  2. WHO Obesityand Overweight Fact sheet No.311. 2016.
  3. Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker S, Clark R, Emberson J, et al. (2009) Body mass indexand cause specific mortalityin 900000 adults: collaborative analysis of 57 prospective studies. Lancet 373(9669): 1083- 1096.
  4. Fried M, Yumuk Y, Oppert JM, Scopinaro N, Torres AJ, et al. (2013) Interdisciplinary guidelines on metabolic and bariatric surgery. Obes Facts 6: 449-468.
  5. Fruhbeck G, Toplak H, Woodward E, Yumuk Y, Maislos M, et al. (2013) Executive Committee of the European Association for the Study of Obesity: Obesity: the gateway to ill health-an EASO position statement on a rising public health, clinical and scientific challenge in Europe. Obes Facts 6(2): 117- 120.
  6. Dyson PA (2010) The therapeutics of lifestyle Management on obesity. Diabetes Obes Metab 12(11): 941-946.
  7. Kulvinder Kochar Kaur, Allahbadia GN, Singh M (2019) Importance of simultaneous treatment of obesity and diabetes mellitus: A sequelae to the understanding of diabesity-A review. Obes Res Open J 6(1): 1-10.
  8. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. (2010) Estmates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12): 2893- 2917.
  9. Steele CB, Thomas CC, Henley SJ, Massetti GM, Galuska DA, et al. (2017) Vital signs: Trends in Incidence of Cancers Associated with Overweight and Obesity-United States. 2005-2014. MMWR Morb Mortal Wkly Rep 66(39): 1052-1058.
  10. Kyrgiou M, Kallialai, Markozannes G, Gunter MJ, Paraskevaidis E, et al. (2017) Adiposity in cancer at major anatomical sites: Umbrella view of the literature. BMJ 356: 477.
  11. Tsugane S, Inoue M (2010) Insulin resistance and cancer: Epidemiological evidence. Cancer Sci 101(5): 1073-1079.
  12. Gunter MJ, Hoover DR, Yu H, Waasertheil-Smoller S, Rohan TE, et al. (2008) Insulin, Insulin-like growth factor1,endogenousestradiol,and risk of colorectal cancer in postmenopausal women. Cancer Res 68(1): 329-327.
  13. Gunter MJ, Hoover DR, Yu H, Waasertheil-Smoller S, Manson JE, et al. (2008) A prospective evaluation of Insulin, and Insulin-like growth factor1 as risk factors for endometrial cancer. Cancer Epidemiol Biomark Prev 17(4): 921-929.
  14. Vona Davis L, Rose DF (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14(2): 189-206.
  15. Grivennikov SL, Greten FR, KIarin M (2010) Immunity, inflammation and cancer. Cell 140(6): 883- 899.
  16. Triantafillidis JK, Nasioulas G, Kosmidis PA (2009) Colorectal cancer and inflammatory bowel disease.Epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res 29(7): 2727-2237.
  17. Zunuga LA, Shen WJ, Joyce-Shaikh B, Pyatnova EA, Richards AG, et al. (2010) IL-17 regulates adipogenesis, glucose homeostasis and obesity. J Immunol 185(11): 6947-6959.
  18. Masters SL, Dunne A, Subramaniam SL, Hull RI, Tannahill GM, et al. (2010) Activation of the NLRP3 inflassome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 11(10): 897-904.
  19. Park EJ, Lee JH, Yu GY, He G, Ali SR, et al. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2): 197-208.
  20. Michelet X, Dyck L, Hogan A, Loftus RM, Duquette D, et al. (2018) Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol 19(12): 1330-1340.
  21. O’Shea D, Corrigan M, Dunne MR, Jackson R, Woods C, et al. (2013) Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection. Int J Obes (Lond) 37(11): 1510-1513.
  22. Boulenuar S, Michelet X, Duquette D, Alvarez D, Hogan AE, et al. (2017) Adipose type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity. Immunity 46(2): 273- 286.
  23. Carolan E, Tobin LM, Mangan BA, Corrigan M, Gaoatswe G, et al. (2015) Altered distribution and increased IL-17 production By mucosal associated invariant T cells in adult and childhood obesity. J Immunol 194(12): 5775-5780.
  24. Carolan E, Hogan AE, Corrigan M, Gaoatswe G, O’Connell J, et al. (2014) The impact of childhood obesity on inflammation, innate immune cell frequency, and metabolic microRNA expression. J Clin Endocrinol Metab 99(3): 474-478.
  25. Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1(1): 41-49.
  26. Morvan MG, Lanier LL (2016) Natural killer cells. You can teach innate cells new tricks. Nat Rev Cancer 16(1): 7-19.
  27. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKGD2 activating receptor. Annu Rev Immunol 31: 413-441.
  28. Ames E, Canter RJ, Grossenbacher SK, Mac S, Chen M, et al. (2015) NK cells preferentially target tumor cells with a Cancer Stem Cell Phenotype. J Immunol 195(8): 4010-4019.
  29. Marcais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, et al. (2014) The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 15(8): 749-757.
  30. Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, et al. (2014) mTORC 1 dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol 193(9): 4477-4784.
  31. Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, et al. (2016) Metabolic reprogramming Supports IFNγ Production by CD56bright NK cells. J Immunol 196(6): 2552-2560.
  32. Sun JC, Belke JN, Lanier LL (2009) Adaptive immune features of Natural killer cells. Nature 457(7229): 557-561.
  33. Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, et al. (2009) Cytokine-induced memory-like Natural killer cells. Proc Natl Acad Soc USA 106(6): 1915- 1919.
  34. Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, et al. (2012) Cytokine activation induces human memory-like NK cells. Blood 120: 4751-4760.
  35. Schantz SP, Shillitoe EJ, Brown B, Campbell B (1986) Natural killer cell activity and head and neck cancer: A clinical assessment. J Natl Cancer Inst 77(4): 869- 875.
  36. Imai K, Matsuyama S, Miyake S, Suga K, Nagachi N (2000) Natural cytotoxic activity and peripheral blood lymphocytes and cancer incidence: An 11 yea follow up study of a general population. Lancet 356(9244): 1795-1799.
  37. Jobin G, Rodriguez-Suarez R, Betito K (2017) Association between Natural killer cell activity and colorectal cancer in high risk subsbjects Undergoing Colonoscopy. Gastroenterology 153(4): 980-987.
  38. Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, et al. (1997) The prognostic significance of intratumoral Natural killer cells in patients with colorectal carcinoma. Cancer 79(12): 3920-3928.
  39. Kaur K, Chang HH, Topchyan P, Cook JM, Barkhordarian A, et al. (2018) Deficiencies in Natural killer cell Numbers ,Expansion and Function at the Pre Neoplastic stage of pancreatic cancer by KRAS Mutation in the Pancreas of Obese Mice. Front Immunol 9: 1229.
  40. Stringaris K, Sekine T, Khoder A, Alsuliman A, Razzaghi B, et al. (2014) Leukemia-induced phenotype and functional defects in Natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 99(5): 836-847.
  41. Mamessier E, Sylvain A, Thibult ML, Houvnaeghel G, Jacquemier J, et al. (2011) Human breast cancer cells enhance self-tolerance by promoting evasion from NK cell antitumor immunity. J Clin Investig 121(9): 3609- 3622.
  42. Guillerey C, Huntington ND, Smyth MJ (2016) Targeting Natural killer cells in cancer immunotherapy. Nat Immunol 17: 1025-1036.
  43. Ruggeri L, Capanni M, Urbani E, Perrucio K, Shlomchik WD, et al. (2002) Effectiveness of donor Natural killer cell alloactivity in mismatched haematopoietic transplants. Science 295(5562): 2097-2100.
  44. Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, et al. (2015) Phase I clinical trial of autologous NK cell therapy using novel expansion methods in patients with advanced digestive cancer. J Transl Med 13: 277.
  45. Parkhurst MR, Riley JP, Dudley ME, Rosenburg SA (2011) Adaptive transfer of autologous Natural killer cells leads to higher levels of circulating Natural killer cells but does not mediate tumor regression. Clin Cancer Res 17(19): 6287-6297.
  46. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, et al. (2005) Successful adaptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105(8): 3051-3057.
  47. Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, et al. (2010) NKAML: A pilot study to determine the safety and feasibility of haploidentical Natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 28(6): 955-959.
  48. Romee R, Rosario M, Berrin-Elliot MM, Wagner JA, Jewell BA, et al. (2016) Cytokine induced memory- like Natural killer cells exhibit enhanced response against myeloid leukemia. Sci Transl Med 8(357): 357ra123.
  49. Lynch LA, O’Connell TJ, Kwasnik AK, Cawood TJ, O’Farrelly C, et al. (2009) Are Natural killer cells protecting the metabolically healthy obese patient?. Obesity 17(3): 601-605.
  50. Viel S, Besson L, Charrier E, Marcais A, Disse E, et al. (2017) Alteration of Natural killer cell phenotype and function in obese individuals. Clin Immunol 177: 12- 17.
  51. Tobin LM, Mavinkurve M, Carolan E, Kinlen D, O’Brien EC, et al. (2017) NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2(24): 94939.
  52. Perdu S, Catellana B, Kim Y, Chan K, DeLuca L, et al. (2016) Maternal obesity drives functional alterations in uterine NK cells. JCI Insight 1(11): e85560.
  53. Moulin CM, Marguti L, Peron JP, Halpern A, Rizzo LV (2011) Bariatric surgery reverses Natural killer(NK) cell activity and NK related cytokine synthesis impairment induced by morbid obesity. Obes Surg 21(1): 112-118.
  54. John J, Spielau M, Brandsch C, Stangl GI, Delank KS, et al. (2015) Decreased NK cell functions in obesity can be reactivated by fat mass reduction. Obesity 23(11): 2233-2241.
  55. Barra NG, Fan LY, Gallen JB, Chew M, Marcinko K, et al. (2017) High intensity interval training increases Natural killer cell number and function in obese breast cancer challenged mice and Obese Women. J Cancer Prev 22(4): 260-266.
  56. Gracey E, Qaiyum Z, Almaghlouth I, Lawson D, Karki S, et al. (2016) IL-17 primes IL-17 in mucosal associated invariant T (MAIT) cells, which contribute to the Th- 17-axis in ankylosing spondylytis. Ann Rheum Dis 75(12): 2124-2132.
  57. Margaret S, Gazzola C, Pegg GG, Hill RA (2002) Leptin: A review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26(11): 1407-1433.
  58. Hogan AE, Gaoatswe G, Lynch L, Corrigan M, Woods C, et al. (2014) Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia 57(4): 781-784.
  59. De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, et al. (2007) A keyrole of leptin in the control of regulatory T cell proliferation. Immunity 26(2): 241- 255.
  60. Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M, et al. (2015) Leptin receptor signaling in T cells are required for Th 17 differentiation. J Immunol 194(11): 5253-5260.
  61. Tian Z, Sun R, Wei H, Gao B (2002) Impaired Natural killer cell (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator of NK cell development and activation. Biochem Biophys Res Commun 298(3): 297-302.
  62. Nave H, Mueller G, Siegmund B, Jacobs R, Stroh T, et al. (2008) Resistance of Janus Kinase -2 dependent leptin signaling in Natural killer cell (NK): A novel mechanism of NK cell dysfunction in diet induced obesity. Endocrinology 149: 3370-3378.
  63. Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70: 537-556.
  64. Laue T, Wrann CD, Hoffmann-Castendiek B, Pietsch D, Hubner L, et al. (2015) Altered NK cell function in obese healthy humans. BMC Obes 2: 1.
  65. AssmannN, O’Brien KL, Donnelly RP, Dyck L, Zaiatz- Bittencourt V, et al. (2017) Srebp-controlled glucose metabolism is essential for NK cell metabolic and functional responses in mice. Nat Commun 18(11): 1197-1206.
  66. Loftus RM, Assmann N, Kedia-Mehta N, O’Brien KL, Garcia A, et al. (2015) Amini acid-dependent CMYC expression is essential for NK cell metabolic and functional responses in mice. Nat Commun 9(1): 2341.
  67. Wensveen FM, Jelencic V, Valentic S, Sestan M, Wensveen TT, et al. (2015) NK cells link obesity- induced adipose stress to inflammation and insulin resistance. Nat Immunol 16(4): 376-385.
  68. O’Sullivan TE, Rapp M, Fan X, Weizman OE, Bhardwaj P, et al. (2016) Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. Immunity 45(2): 428-441.
  69. Lee BC, Kim MS, Pae M, Yamamoto Y, Eberie D, et al. (2016) Adipose Natural killer cells Regulate Adipose tissue Macrophages to Promote Insulin Resistance in Obesity. Cell Metab 23(4): 685-698.
  70. O’Rourke RW, Gaston GD, Meyer KA, White AE, Marks DL (2013) Adipose tissue NK cells manifest an activated phenotype in human obesity. Metabolism 62(11): 1557-1561.
  71. O’Rourke RW, Meyer KA, Neeley CK, Gaston GD, Sekhri P, et al. (2014) Systemic NK cell ablation attenuates intra-abdominal Adipose tissue Macrophage infiltration in murine obesity. Obesity 22(10): 2109-2114.
  72. Sasaki T, Moro K, Kubola T, Kubola N, Kato T, et al. (2019) Innate Lymphoid cells in the Induction of Obesity. Cell Rep 28(1): 202-217.
  73. Rakshandehroo M, vanEijkeren RJ, Gabriel TL, De Haar C, Gilzel SMW, et al. (2019) Adipocytes harbor a glucosyl ceramide biosynthesis pathway involved in INKT activation. Biochim Biophys Acta Mol Cell Biol Lipids 1864(8): 1157-1167.
  74. O’Shea D, Hogan AE (2019) Dysregulation of natural killer cells in Obesity. Cancers 11(4): 573.
More from this journal

Cite this article

BibTeX
APA
RIS
@article{kulvinder2019,
  title   = {Alteration in Natural Killer (NK) cell Function in Obesity-correlating with comorbidities development like cancer and type 2 diabetes-A Minireview},
  author  = {Kulvinder Kochar Kaur, Allahbadia G and Mandeep Singh},
  journal = {Open Access Journal of Endocrinology},
  year    = {2019},
  volume  = {3},
  number  = {2},
  doi     = {10.23880/oaje-16000140}
}
Kulvinder Kochar Kaur, Allahbadia G and Mandeep Singh (2019). Alteration in Natural Killer (NK) cell Function in Obesity-correlating with comorbidities development like cancer and type 2 diabetes-A Minireview. Open Access Journal of Endocrinology, 3(2). https://doi.org/10.23880/oaje-16000140
TY  - JOUR
TI  - Alteration in Natural Killer (NK) cell Function in Obesity-correlating with comorbidities development like cancer and type 2 diabetes-A Minireview
AU  - Kulvinder Kochar Kaur, Allahbadia G and Mandeep Singh
JO  - Open Access Journal of Endocrinology
PY  - 2019
VL  - 3
IS  - 2
DO  - 10.23880/oaje-16000140
ER  -