ABSTRACT
CONTEXT: Activity of delta-9, delta-6, and delta-5 desaturases (D9D, D6D, D5D) are associated with obesity, insulin resistance, and dyslipidemia. OBJECTIVE: To investigate the association of estimated desaturase activities with weight status, insulin resistance, and dyslipidemia in children, cross-sectionally and longitudinally. DESIGN: The IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) cohort study was used, with examinations at baseline (T0) and after 2 years (T1). SETTING AND PARTICIPANTS: Children aged 2 to less than 10 years from eight European countries were recruited in kindergartens/primary schools. Children with available data on fatty acids, outcome, and covariate information were included in the analyses. METHODS: Whole blood fatty acids were analyzed in 2600 children at baseline. D9D (16:1n-7/16:0), D6D (20:3n-6/18:2n-6), and D5D (20:4n-6/20:3n-6) activities were estimated from product-precursor fatty acids ratios. Body mass index (BMI), Homeostatic Model Assessment index, and high-density lipoprotein cholesterol (HDL), and triglycerides (TG) served as outcomes for weight status, insulin resistance, and dyslipidemia, respectively. Linear and logistic regression and repeated measures models were used to assess the cross-sectional and longitudinal associations between desaturase activity and outcomes. RESULTS: In the cross-sectional analysis, D9D and D6D were positively associated with BMI and TG z-scores and inversely with HDL z-scores. D5D was inversely associated with BMI and TG z-scores (ie, a D5D increase of 1 unit is associated with a BMI z-score decrease of 0.07 and a 28% lower odds ratio for TG ≥ 75th percentile). Longitudinally, similar associations were found for T0 desaturase activities with BMI and for T0 D6D with HDL at follow-up (T1). Baseline D6D and D5D were positively associated with the change of HDL z-score from T0 to T1, and D6D with the change of Homeostatic Model Assessment index z-score. CONCLUSION: Desaturase activities are associated with metabolic risk markers already in young children and appear to predict the metabolic risk.
Subject(s)
Body Weight/physiology , Fatty Acid Desaturases/metabolism , Fatty Acids/blood , Insulin Resistance/physiology , Triglycerides/blood , Biomarkers , Body Mass Index , Child , Child, Preschool , Cross-Sectional Studies , Delta-5 Fatty Acid Desaturase , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/physiopathology , Female , Humans , Male , Metabolic Syndrome/blood , Metabolic Syndrome/diagnosis , Metabolic Syndrome/physiopathology , Risk FactorsABSTRACT
Caveolin-1 (Cav-1) is highly expressed in alveolar epithelial type I (AE1) and endothelial cells of the alveolar region of the lung. Interestingly, alveolar epithelial type II (AE2) cells that are progenitors of the AE1 cells do not express Cav-1. We investigated whether genetic Cav-1 deficiency alters the phenotype of AE2 cells and their microenvironment using stereology. Total number, mean volume, and subcellular composition of the AE2 cells were not altered in Cav-1(-/-) when compared with wild-type mice. The alveolar septa were thickened and contained a significantly greater volume of extracellular matrix. Thus, AE2 cells as progenitors of AE1 cells are not critically involved in the severe pulmonary phenotype in Cav-1-deficient mice.
Subject(s)
Alveolar Epithelial Cells/cytology , Caveolin 1/deficiency , Cellular Microenvironment/physiology , Alveolar Epithelial Cells/metabolism , Animals , Caveolae/metabolism , Caveolin 1/genetics , Extracellular Matrix/metabolism , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Stem Cells/cytology , Stem Cells/metabolismABSTRACT
Cholinergic bronchoconstriction is mediated by M(2) and M(3) muscarinic receptors (MR). In heart and urinary bladder, MR are linked to caveolin-1 or -3, the structural proteins of caveolae. Caveolae are cholesterol-rich, omega-shaped invaginations of the plasma membrane. They provide a scaffold for multiple G protein receptors and membrane-bound enzymes, thereby orchestrating signaling into the cell interior. Hence, we hypothesized that airway MR signaling pathways are coupled to caveolae as well. To address this issue, we determined the distribution of caveolin isoforms and MR subtype M2R in murine and human airways and investigated protein-protein associations by fluorescence resonance energy transfer (FRET)-confocal laser scanning microscopy (CLSM) analysis in immunolabeled murine tissue sections. Bronchoconstrictor responses of murine bronchi were recorded in lung-slice preparations before and after caveolae disruption by methyl-ß-cyclodextrin, with efficiency of this treatment being validated by electron microscopy. KCl-induced bronchoconstriction was unaffected after treatment, demonstrating functional integrity of the smooth muscle. Caveolae disruption decreased muscarine-induced bronchoconstriction in wild-type and abolished it in M2R(-/-) and M3R(-/-) mice. Thus M2R and M3R signaling pathways require intact caveolae. Furthermore, we identified a presumed skeletal and cardiac myocyte-specific caveolin isoform, caveolin-3, in human and murine bronchial smooth muscle and found it to be associated with M2R in situ. In contrast, M2R was not associated with caveolin-1, despite an in situ association of caveolin-1 and caveolin-3 that was detected. Here, we demonstrated that M2R- and M3R-mediated bronchoconstriction is caveolae-dependent. Since caveolin-3 is directly associated with M2R, we suggest caveolin-3 as novel regulator of M2R-mediated signaling.
