Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes

Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes

Bouncing back: Using a complex dynamical systems approach to measure physical resilience in older adults

Contains fulltext : 215259.pdf (publisher's version ) (Open Access)Radboud University, 5 februari 2020Promotores : Olde Rikkert, M.G.M., Scheffer, M Co-promotores : Melis, R.J.F., Leemput, I. van d

An exploration of the concept and operationalization of resilience in medicine

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Dynamical Resilience Indicators in Time Series of Self-Rated Health Correspond to Frailty Levels in Older Adults

Background: We currently still lack valid methods to dynamically measure resilience for stressors before the appearance of adverse health outcomes that hamper well-being. Quantifying an older adult's resilience in an early stage would aid complex decision-making in health care. Translating complex dynamical systems theory to humans, we hypothesized that three dynamical indicators of resilience (variance, temporal autocorrelation, and cross-correlation) in time series of self-rated physical, mental, and social health were associated with frailty levels in older adults. Methods: We monitored self-rated physical, mental, and social health during 100 days using daily visual analogue scale questions in 22 institutionalized older adults (mean age 84.0, SD: 5.9 years). Frailty was determined by the Survey of Health, Ageing and Retirement in Europe (SHARE) frailty index. The resilience indicators (variance, temporal autocorrelation, and cross-correlation) were calculated using multilevel models. Results: The self-rated health time series of frail elderly exhibited significantly elevated variance in the physical, mental, and social domain, as well as significantly stronger cross-correlations between all three domains, as compared to the nonfrail group (all P < 0.001). Temporal autocorrelation was not significantly associated with frailty. Conclusions: We found supporting evidence for two out of three hypothesized resilience indicators to be related to frailty levels in older adults. By mirroring the dynamical resilience indicators to a frailty index, we delivered a first empirical base to validate and quantify the construct of systemic resilience in older adults in a dynamic way

Orthostatic blood pressure measurements as predictors of recovery after hospitalization

Failure to recover from blood pressure decline in the first minute after active standing up is associated with all-cause mortality in geriatric outpatients. We aimed to study if recovery times upon an orthostatic challenge and blood pressure variability could predict recovery outcomes of hospital admission in geriatric inpatients. In this talk, the results of an observational prospective study of 121 patients hospitalized in the geriatric ward (aged 84.3 ± 6.2 years, 60% female) will be presented. During the hospital stay, blood pressure and heart rate were monitored during a 7-minute orthostatic challenge test using a Finometer (Finapres). Heart rate and blood pressure variance, temporal autocorrelation, and recovery times will be related to the level of functional recovery measured with the TOPICS-MDS questionnaire or death (n=32) at 3-months follow-up. This work contributes to the development of clinically relevant and feasible dynamic tests of physical resilience

Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Contains fulltext : 207077.pdf (publisher's version ) (Open Access

Measurement of Dynamical Resilience Indicators Improves the Prediction of Recovery Following Hospitalization in Older Adults

Contains fulltext : 217763.pdf (Publisher’s version ) (Closed access