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

Bähr, Ina; Goritz, Vincent; Doberstein, Henriette; Hiller, Grit Gesine Ruth; Rosenstock, Philip; Jahn, Janine; Pörtner, O.J.; Berreis, Tobias; Mueller, Thomas; Spielmann, Julia; Kielstein, Heike

doi:10.1155/2017/4297025

Cited by 54 publications

(78 citation statements)

References 60 publications

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“…Interestingly, our own studies demonstrated a leptininduced reduction of IFN-γ secretion in primary human NK cells but not in NK-92 cells. In addition, the data point toward a decreased basal lytic activity against target cells in NK-92 cells compared to primary NK cells (93). Although NK cell lines, like NK-92, are well-established human models for investigations on NK cell functionality and exhibit phenotypical and functional characteristics of primary NK cells, these data underline the limited transferability of findings obtained using immortalized cell lines to conclude the mode of action of primary NK cells (93,95,96).…”

Section: Studies On Leptinmentioning

confidence: 88%

“…In addition, the data point toward a decreased basal lytic activity against target cells in NK-92 cells compared to primary NK cells (93). Although NK cell lines, like NK-92, are well-established human models for investigations on NK cell functionality and exhibit phenotypical and functional characteristics of primary NK cells, these data underline the limited transferability of findings obtained using immortalized cell lines to conclude the mode of action of primary NK cells (93,95,96). Furthermore, results showed that the leptin effects on NK cells are more pronounced using higher leptin concentrations for incubation experiments (67,93).…”

Section: Studies On Leptinmentioning

confidence: 90%

“…Although NK cell lines, like NK-92, are well-established human models for investigations on NK cell functionality and exhibit phenotypical and functional characteristics of primary NK cells, these data underline the limited transferability of findings obtained using immortalized cell lines to conclude the mode of action of primary NK cells (93,95,96). Furthermore, results showed that the leptin effects on NK cells are more pronounced using higher leptin concentrations for incubation experiments (67,93). These findings indicate that leptin negatively affects NK cell activity primarily in pathologically elevated leptin concentrations as determined in obese individuals.…”

Section: Studies On Leptinmentioning

confidence: 98%

“…All these studies have been performed using the human myelogenous leukemia line K652 or the murine lymphoma cell line YAC-1 as target cells for cytotoxicity assays. Interestingly, data using other target cells, like colon or breast cancer cells, revealed evidence for a decreased cytotoxicity of NK cells upon leptin treatment (67,93). Therefore, the influence of leptin on NK cell cytolysis may depend on the tumor target cells, most likely based on their differential NK cell ligand profile.…”

Section: Studies On Leptinmentioning

confidence: 99%

“…On the one hand, some studies demonstrated a stimulating leptin effect on the metabolic activity, mRNA expression or release of perforin, granzyme A, IFNγ, TRAIL, FasL, and leptin receptors of NK cells (67)(68)(69)94). On the other hand, leptin had been shown to decrease IFN-γ secretion, mRNA expression of the activating NK cell receptors NKG2D and NKp46, and the activation marker CD69 as well as the FasL and TRAIL mRNA expression (67,69,93). Other studies did not find leptin-related effects on granzyme and perforin secretion nor degranulation marker CD107a, IFN-γ, or FasL mRNA expression (68,69).…”

Section: Studies On Leptinmentioning

confidence: 99%

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Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

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Section: Studies On Leptinmentioning

confidence: 88%

Section: Studies On Leptinmentioning

confidence: 90%

Section: Studies On Leptinmentioning

confidence: 98%

Section: Studies On Leptinmentioning

confidence: 99%

Section: Studies On Leptinmentioning

confidence: 99%

See 3 more Smart Citations

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Immune cell profile and immune‐related gene expression of obese peripheral blood and liver tissue

Taylor

McLachlan

2021

FEBS Letters

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Obesity is associated with changes in immune cell subpopulations. However, tissue and blood obesity‐responsive immune phenotypic pathways have not been contrasted. Here, the local niche immune cell population and gene expression in fatty liver is compared to peripheral blood of obese individuals. The Cibersort algorithm enumerated increased fractions of memory CD4+ T lymphocytes and reductions in natural killer and memory B cells in obese liver tissue and obese blood, with similar reductions found in nonalcoholic fatty liver disease tissue. Gene expression analysis identified inflammatory immune signatures of regulatory CD4+ T cells with inferred Th1, Th17, Th2, or Treg phenotypes that differed between liver and blood. Our study suggests that the local tissue‐specific immune phenotype in the liver differs from the obese peripheral circulation, with the latter reflective of multisystemic persistent inflammation that is characteristic of obesity.

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Glucagon‐like peptide‐1 therapy in people with obesity restores natural killer cell metabolism and effector function

Barra

Mat

O’Donnell

et al. 2023

Obesity

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Objective People with obesity (PWO) have functionally defective natural killer (NK) cells, with a decreased capacity to produce cytokines and kill target cells, underpinned by defective cellular metabolism. It is plausible that the changes in peripheral NK cell activity are contributing to the multimorbidity in PWO, which includes an increased risk of cancer. This study investigated whether therapy with long‐acting glucagon‐like peptide‐1 (GLP‐1) analogues, which are an effective treatment for obesity, could restore NK cell functionality in PWO. Methods In a cohort of 20 PWO, this study investigated whether 6 months of once weekly GLP‐1 therapy (semaglutide) could restore human NK cell function and metabolism using multicolor flow cytometry, enzyme‐linked immunosorbent assays, and cytotoxicity assays. Results These data demonstrate that PWO who received GLP‐1 therapy have improved NK cell function, as measured by cytotoxicity and interferon‐γ/granzyme B production. In addition, the study demonstrates increases in a CD98‐mTOR‐glycolysis metabolic axis, which is critical for NK cell cytokine production. Finally, it shows that the reported improvements in NK cell function appear to be independent of weight loss. Conclusions The restoration, by GLP‐1 therapy, of NK cell functionality in PWO may be contributing to the overall benefits being seen with this class of medication.

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

Cited by 54 publications

References 60 publications

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Immune cell profile and immune‐related gene expression of obese peripheral blood and liver tissue

Glucagon‐like peptide‐1 therapy in people with obesity restores natural killer cell metabolism and effector function

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