High-throughput proteomics uncovers exercise training and type 2 diabetes-induced changes in human white adipose tissue.

White adipose tissue (WAT) is important for metabolic homeostasis. We established the differential proteomic signatures of WAT in glucose-tolerant lean and obese individuals and patients with type 2 diabetes (T2D) and the response to 8 weeks of high-intensity interval training (HIIT). Using a high-throughput and reproducible mass spectrometry-based proteomics pipeline, we identified 3773 proteins and found that most regulated proteins displayed progression in markers of dysfunctional WAT from lean to obese to T2D individuals and were highly associated with clinical measures such as insulin sensitivity and HbA1c.

CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle.

Objective: The AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The main upstream kinase that activates AMPK through phosphorylation of α-AMPK Thr172 in skeletal muscle is LKB1, however some studies have suggested that Ca/calmodulin-dependent protein kinase kinase 2 (CaMKK2) acts as an alternative kinase to activate AMPK. We aimed to establish whether CaMKK2 is involved in activation of AMPK and promotion of glucose uptake following contractions in skeletal muscle.

TBC1D4-S711 Controls Skeletal Muscle Insulin Sensitization After Exercise and Contraction.

The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise, and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation.

Dose and route of administration determine the efficacy of prophylactic immunotherapy for peanut allergy in a Brown Norway rat model.

Introduction: Allergen-specific immunotherapy (IT) is emerging as a viable option for treatment of peanut allergy. Yet, prophylactic IT remains unexplored despite early introduction of peanut in infancy was shown to prevent allergy. There is a need to understand how allergens interact with the immune system depending on the route of administration, and how different dosages of allergen may protect from sensitisation and a clinical active allergy.

The role of skin inflammation, barrier dysfunction, and oral tolerance in skin sensitization to gluten-derived hydrolysates in a rat model.

Background: Adverse reactions to wheat-containing skin care products have been linked to food allergy development.

Objectives: To determine the role of skin barrier dysfunction and inflammation in sensitization to gluten-derived hydrolysates via the skin in Brown Norway rats with and without oral tolerance to wheat.

Methods: Skin barrier defect was induced by mechanical disruption, and skin inflammation was induced by topical application of SLS or MC903.

High-intensity interval training remodels the proteome and acetylome of human skeletal muscle.

Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins.

Timing and Causes of Death in Acute Myocardial Infarction Complicated by Cardiogenic Shock (from the RETROSHOCK Cohort).

Acute myocardial infarction complicated by cardiogenic shock (AMICS) comprises a heterogeneous population with high mortality. Insight in timing and cause of death may improve understanding of the condition and aid individualization of treatment. This was assessed in a retrospective, multicenter observational cohort study based on 1,716 patients with AMICS treated during the period of 2010 to 2017, of whom 904 died before hospital discharge.

Illumination of the Endogenous Insulin-Regulated TBC1D4 Interactome in Human Skeletal Muscle.

Insulin-stimulated muscle glucose uptake is a key process in glycemic control. This process depends on the redistribution of glucose transporters to the surface membrane, a process that involves regulatory proteins such as TBC1D1 and TBC1D4. Accordingly, a TBC1D4 loss-of-function mutation in human skeletal muscle is associated with an increased risk of type 2 diabetes, and observations from carriers of a TBC1D1 variant associate this protein to a severe obesity phenotype.

Amoxicillin does not affect the development of cow's milk allergy in a Brown Norway rat model.

The use of antibiotics as well as changes in the gut microbiota have been linked to development of food allergy in childhood. It remains unknown whether administration of a single clinically relevant antibiotic directly promotes food allergy development when administrated during the sensitisation phase in an experimental animal model. We investigated whether the antibiotic amoxicillin affected gut microbiota composition, development of cow's milk allergy (CMA) and frequencies of allergic effector cells and regulatory T cells in the intestine.

Acid Hydrolysis of Gluten Enhances the Skin Sensitizing Potential and Drives Diversification of IgE Reactivity to Unmodified Gluten Proteins.

Scope: Personal care products containing hydrolyzed gluten have been linked to spontaneous sensitization through the skin, however the impact of the hydrolysate characteristics on the sensitizing capacity is generally unknown.

Methods And Results: The physicochemical properties of five different wheat-derived gluten products (one unmodified, one enzyme hydrolyzed, and three acid hydrolyzed) are investigated, and the skin sensitizing capacity is determined in allergy-prone Brown Norway rats. Acid hydrolyzed gluten products exhibited the strongest intrinsic sensitizing capacity via the skin.

Partially Hydrolysed Whey Has Superior Allergy Preventive Capacity Compared to Intact Whey Regardless of Amoxicillin Administration in Brown Norway Rats.

Background: It remains largely unknown how physicochemical properties of hydrolysed infant formulas influence their allergy preventive capacity, and results from clinical and animal studies comparing the preventive capacity of hydrolysed infant formula with conventional infant formula are inconclusive. Thus, the use of hydrolysed infant formula for allergy prevention in atopy-prone infants is highly debated. Furthermore, knowledge on how gut microbiota influences allergy prevention remains scarce.

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice.

Skeletal muscle is an insulin-responsive tissue and typically takes up most of the glucose that enters the blood after a meal. Moreover, it has been reported that skeletal muscle may increase the extraction of glucose from the blood by up to 50-fold during exercise compared to resting conditions. The increase in muscle glucose uptake during exercise and insulin stimulation is dependent on the translocation of glucose transporter 4 (GLUT4) from intracellular compartments to the muscle cell surface membrane, as well as phosphorylation of glucose to glucose-6-phosphate by hexokinase II.

Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma.

Background: Several childhood asthma risk loci that relate to immune function have been identified by genome-wide association studies (GWAS), but the underlying mechanisms remain unknown.

Objective: Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma.

Methods: Peripheral blood mononuclear cells from 336 six-month-old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC ) cohort were stimulated in vitro with six different innate ligands (LPS, CpG, poly(I:C), R848, HDMAPP and aluminium hydroxide together with low levels of LPS) followed by quantification of 18 released cytokines and chemokines 40 h after the stimulations.

Quinoa (Chenopodium quinoa Willd.) Seeds Increase Intestinal Protein Uptake.

Scope: Within the last decade, quinoa seeds have gained much popularity as a new food and have recently been proposed as an appropriate food for early introduction in infants. Quinoa contains high levels of saponins, which are known for their adjuvant activity and effect on the intestinal barrier function. The aim of this study is to investigate the impact of quinoa on intestinal permeability and inflammation in comparison with the positive controls; cholera toxin (CT), and capsaicin.

Production of allergen-specific immunotherapeutic agents for the treatment of food allergy.

Allergen-specific immunotherapy (IT) is emerging as a viable avenue for the treatment of food allergies. Clinical trials currently investigate raw or slightly processed foods as therapeutic agents, as trials using food-grade agents can be performed without the strict regulations to which conventional drugs are subjected. However, this limits the ability of standardization and may affect clinical trial outcomes and reproducibility.

Inducible deletion of skeletal muscle AMPKα reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise.

Objective: Evidence for AMP-activated protein kinase (AMPK)-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to a chronic lack of AMPK function. To study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice.

Short-Term Amoxicillin-Induced Perturbation of the Gut Microbiota Promotes Acute Intestinal Immune Regulation in Brown Norway Rats.

The intestinal gut microbiota is essential for maintaining host health. Concerns have been raised about the possible connection between antibiotic use, causing microbiota disturbances, and the increase in allergic and autoimmune diseases observed during the last decades. To elucidate the putative connection between antibiotic use and immune regulation, we have assessed the effects of the antibiotic amoxicillin on immune regulation, protein uptake, and bacterial community structure in a Brown Norway rat model.

Distinct immune phenotypes in infants developing asthma during childhood.

Early exposure to environmental triggers may elicit trajectories to chronic inflammatory disease through deregulated immune responses. To address relations between early immune competence and development of childhood asthma, we performed functional immune profiling of 186 parameters in blood of 541 18-month-old infants and examined links between their response phenotype and development of transient or persistent disease at 6 years of age. An abnormal neutrophil-linked antiviral response was associated with increased risk of transient asthma.

Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice.

Cyclooxygenases are known as important regulators of metabolism and immune processes via conversion of C20 fatty acids into various regulatory lipid mediators, and cyclooxygenase activity has been implicated in browning of white adipose tissues. We generated transgenic (TG) C57BL/6 mice expressing the Ptgs2 gene encoding cyclooxygenase-2 (COX-2) in mature adipocytes. TG mice fed a high-fat diet displayed marginally lower weight gain with less hepatic steatosis and a slight improvement in insulin sensitivity, but no difference in glucose tolerance.

TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction.

Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK is necessary for AICAR, contraction, and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization.