Human NK Cell Subset Functions Are Differentially Affected by Adipokines

Background: Obesity is a risk factor for various types of infectious diseases and cancer. The increase in adipose tissue causes alterations in both adipogenesis and the production of adipocyte-secreted proteins (adipokines). Since natural killer (NK) cells are the host’s primary defense against virus-infected and tumor cells, we investigated how adipocyte-conditioned medium (ACM) affects functions of two distinct human NK cell subsets. Methods: Isolated human peripheral blood mononuclear cells (PBMCs) were cultured with various concentrations of human and murine ACM harvested on two different days during adipogenesis and analyzed by fluorescent-activated cell sorting (FACS). Results: FACS analyses showed that the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), granzyme A (GzmA) and interferon (IFN)-γ in NK cells was regulated in a subset-specific manner. ACM treatment altered IFN-γ expression in CD56dim NK cells. The production of GzmA in CD56bright NK cells was differentially affected by the distinct adipokine compositions harvested at different states of adipogenesis. Comparison of the treatment with either human or murine ACM revealed that adipokine-induced effects on NK cell expression of the leptin receptor (Ob-R), TRAIL and IFN-γ were species-specific. Conclusion: Considering the growing prevalence of obesity and the various disorders related to it, the present study provides further insights into the roles human NK cell subsets play in the obesity-associated state of chronic low-grade inflammation

Cardiorespiratory Fitness and Insulin Sensitivity in Overweight or Obese Subjects May Be Linked Through Intrahepatic Lipid Content

Objective: Low cardiorespiratory fitness predisposes to cardiovascular disease and type 2 diabetes mellitus in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL. Research Design and Methods: We included 138 overweight to obese, otherwise healthy subjects (age: 43.6 +/- 8.9 yrs., body mass index: 33.8 +/- 4 kg/m(2)). Body composition was estimated by bio-impedance analyses. Abdominal fat distribution, intramyocellular, and intrahepatic lipid content were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate individual's cardiorespiratory fitness. Insulin sensitivity was determined during an oral glucose tolerance test. Results: For all subjects, cardiorespiratory fitness was related to insulin sensitivity (r=0.32, p<0.05), IHL (r=-0.27, p<0.05), visceral (r=-0.25, p<0.05) and total fat mass (r=-0.32, p<0.05), but not to intramyocellular lipids (r=-0.08, ns). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat and fitness (r(2)=-0.43, p<0.01; r(2)=-0.34 and r(2)=0.29, p<0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r=0.16, ns), whereas it remained significant when adjusted for visceral- or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels. Conclusions: Our study suggests that the positive effect of increased cardiorespiratory fitness in overweight to obese subjects on insulin sensitivity may be mediated indirectly through IHL reduction

Liver Afferents Contribute to Water Drinking-Induced Sympathetic Activation in Human Subjects: A Clinical Trial

Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant) as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant) as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (p<0.05 between groups) after 30–40 minutes of water drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects

Expression der Gene des Renin-Angiotensin Systems humaner Adipocyten bei adipositas-assoziierter Hypertonie

Hypertonie ist die häufigste adipositas-assoziierte Erkrankung. Das vermehrt vorhandene Fettgewebe könnte von pathophysiologischer Bedeutung sein, da es eine Reihe von Substanzen sezerniert, die die Blutdruckregulation beeinflussen. Hinweise auf eine Rolle des adipocytären Renin-Angiotensin Systems für die Hypertonie ergeben sich aus der Assoziation von Adipositas und einer gesteigerten systemischen Aktivität des Renin-Angiotensin Systems, sowie aus dem Nachweis im Tiermodell, dass adipocytär gebildetes Angiotensinogen in die systemische Zirkulation gelangt. In der vorliegenden Untersuchung wurden 12 schlanke Normotonikerinnen, 8 adipöse Normotonikerinnen und 10 adipöse Hypertonikerinnen charakterisiert und die adipocytäre Genexpression des Renin-Angiotensin Systems untersucht. Adipocyten wurden mittels Nadelbiopsie und Kollagenaseverdau gewonnen, die Genexpression wurde durch real-time RT-PCR bestimmt. Der Vergleich der drei Gruppen zeigt, dass Adipositas mit einer Reduktion der Angiotensinogen-Expression einhergeht, die adipositas-assoziierte Hypertonie mit einer gesteigerten Expression von Renin, Angiotensin-Converting-Enzyme und Angiotensin II-Typ 1-Rezeptor. Dies führt zu der Hypothese, dass im Fettgewebe adipöser Hypertoniker vermehrt Angiotensin II gebildet wird und könnte den positiven Einfluß von ACE-Hemmern auf die Insulinresistenz und die Verringerung der Neuerkrankungsrate an Diabetes mellitus Typ 2 erklären.Adipose tissue secretes vasoactive substances which may contribute to the development of obesity-related hypertension. We aimed to study the differential expression of renin-angiotensin system genes in subcutaneous abdominal adipocytes of 12 lean normotensive, 8 obese normotensive, and 10 obese hypertensive women in a cross-sectional study. 24h ambulatory blood pressure measurement, clinical chemistry, and anthropometry were used to characterize the volunteers. Adipocytes were obtained by abdominal subcutaneous needle biopsy and collagenase digestion. Gene expression was studied by quantitative real time RT-PCR. While expression of the angiotensinogen gene was significantly lower in adipocytes from both obese groups, the renin, angiotensin-converting enzyme and angiotensin II-type 1-receptor genes were significantly upregulated in obese hypertensives. In conclusion, renin-angiotensin system genes are differentially regulated in human obesity and hypertension. The data obtained suggest increased formation of angiotensin II in adipose tissue of obese hypertensive subjects. The role of the adipose-tissue renin-angiotensin system in the development of obesity-associated hypertension or metabolic disease clearly warrants further study