Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagenbinding integrin, a2b1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrinlinked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of b-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK lox/lox ) and muscle-specific ILK-deficient (ILK lox/lox HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK lox/lox and ILK lox/lox HSAcre mice. However, HF-fed ILK lox/lox HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK lox/lox mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK lox/lox HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.Insulin resistance is a commonly associated risk factor for many pathophysiological conditions, including diabetes, cardiovascular diseases, neurological changes, liver diseases, and sleep apnea (1,2). A defect in glucose utilization in the skeletal muscle is a major component of insulin resistance. The pathogenesis of muscle insulin resistance is not fully understood, and pharmacological interventions that reduce insulin resistance are limited and often lose efficacy over time (e.g., biguanides) or have adverse side effects (e.g., thiazolidinediones) (3). Our recent studies have suggested a novel role for extramyocellular factors in regulating muscle insulin action. Expansion of extracellular matrix (ECM) components, such as the collagens and the expression of the collagen-binding integrin a2b1, are associated with muscle insulin resistance induced by a high-fat (HF) diet (4). The ECM is in direct contact with the muscle capillaries. Defects in recruitment of muscle capillaries contribute to the development of muscle insulin resistance (5). Transduction of ECM signals through integrins requires interaction of the integrin cytoplasmic domains with cellular proteins. To investigate the link between ECM-integrin signaling and muscle insulin resistance, we studied a highly conserved central downstream component of the ECM-integrin signaling, integrin-linked kinase (ILK), and its role in muscle insulin resistance.ILK, a pseudokinase with adaptor function, is a central component of the ILK-PINCH-parvin complex (IPP) (6). This complex binds to the cytoplasmic domain of b-integrin subunits. The IPP co...
Many humans lack sufficient zinc (Zn) in their diet for their wellbeing and increasing Zn concentrations in edible produce (biofortification) can mitigate this. Recent efforts have focused on biofortifying staple crops. However, greater Zn concentrations can be achieved in leafy vegetables than in fruits, seeds, or tubers. Brassicas, such as cabbage and broccoli, are widely consumed and might provide an additional means to increase dietary Zn intake. Zinc concentrations in brassicas are limited primarily by Zn phytotoxicity. To assess the limits of Zn biofortification of brassicas, the Zn concentration in a peat:sand (v/v 75:25) medium was manipulated to examine the relationship between shoot Zn concentration and shoot dry weight (DW) and thereby determine the critical shoot Zn concentrations, defined as the shoot Zn concentration at which yield is reduced below 90%. The critical shoot Zn concentration was regarded as the commercial limit to Zn biofortification. Experiments were undertaken over six successive years. A linear relationship between Zn fertiliser application and shoot Zn concentration was observed at low application rates. Critical shoot Zn concentrations ranged from 0.074 to 1.201 mg Zn g −1 DW among cabbage genotypes studied in 2014, and between 0.117 and 1.666 mg Zn g −1 DW among broccoli genotypes studied in 2015-2017. It is concluded that if 5% of the dietary Zn intake of a population is currently delivered through brassicas, then the biofortification of brassicas from 0.057 to > 0.100 mg Zn g −1 DW through the application of Zn fertilisers could increase dietary Zn intake substantially.
We have compared the phenotypic and functional characteristics of dendritic cells (DC) generated in vitro from the peripheral blood mononuclear fraction of myelodysplastic syndrome (MDS) patients (four refractory anaemia, four refractory anaemia with excess of blasts) with DCs generated in a similar way from eight healthy donors. After 10 d of culture in the presence of GM-CSF and IL-4, reduced numbers and percentages of DCs were obtained in MDS subjects. MDS DCs exhibited significantly lower expression of CD1a, CD54, CD80 and MHC class II molecules. Their ability to stimulate T lymphocytes in an allogeneic mixed leucocyte reaction was reduced in comparison to normal subjects. Furthermore, MDS DCs also showed a reduced receptor-mediated endocytosis as demonstrated by FITC-dextran uptake. Simultaneous fluorescence in situ hybridization (FISH) and immunophenotypic analysis demonstrated that MDS DCs have the same cytogenetic abnormality of the malignant clone. Taken together these findings indicate that, in MDS, DCs are part of the malignant clone and exhibit a deficient antigen uptake and presentation.
Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.
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