Externalized phosphatidylinositides on apoptotic cells are eat-me signals recognized by CD14.

Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14 phagocytes.

NFκB Regulates Muscle Development and Mitochondrial Function.

Nuclear factor (NF)κB is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NFκB has been implicated in the regulation of metabolic processes and tissue mass, yet its affects on mitochondrial function in this tissue are unclear. To investigate the role of NFκB on mitochondrial function and its relationship with muscle mass across the life span, we study a mouse model with muscle-specific NFκB suppression (muscle-specific IκBα super-repressor [MISR] mice).

Sustained NFκB inhibition improves insulin sensitivity but is detrimental to muscle health.

Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them.

The carboxy-terminal region of the TBC1D4 (AS160) RabGAP mediates protein homodimerization.

TBC1D4 (also known as AS160) is a Rab·GTPase-activating protein (RabGAP) which functions in insulin signaling. TBC1D4 is critical for translocation of glucose transporter 4 (GLUT4), from an inactive, intracellular, vesicle-bound site to the plasma membrane, where it promotes glucose entry into cells. The TBC1D4 protein is structurally subdivided into two N-terminal phosphotyrosine-binding (PTB) domains, a C-terminal catalytic RabGAP domain, and a disordered segment in between containing potential Akt phosphorylation sites.

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

Objective: To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease.

Methods: Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial.

Results: Participants were mostly Caucasian males, age 60±7 years, BMI 31.

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk.

Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing.

Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.

Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage.

Effect of Targeting Inflammation With Salsalate: The TINSAL-CVD Randomized Clinical Trial on Progression of Coronary Plaque in Overweight and Obese Patients Using Statins.

Importance: Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease.

Objective: To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque.

Design, Setting, And Participants: In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies.

Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity.

Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots.

Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1.

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms.

Muscle-specific inhibition of the classical nuclear factor-κB pathway is protective against diaphragmatic weakness in murine endotoxemia.

Objective: Diaphragmatic weakness and acute respiratory failure are common in sepsis. Nuclear factor-κB acts as a general coordinator of the systemic inflammatory response, but its role within the diaphragm itself during sepsis is unknown. We investigated the potential protective effect upon the diaphragm of inhibiting nuclear factor-κB only within muscle fibers during acute endotoxemia.

Insulin receptor activation with transmembrane domain ligands.

Complementary surfaces are buried when peptide hormones, growth factors, or cytokines bind and activate cellular receptors. Although these extended surfaces provide high affinity and specificity to the interactions, they also present great challenges to the design of small molecules that might either mimic or antagonize the process. We show that the insulin receptor (IR) and downstream signals can be activated by targeting a site outside of its ligand-binding domain.

Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models.

The impact of salsalate treatment on serum levels of advanced glycation end products in type 2 diabetes.

OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters.

Sustained NF-κB activation and inhibition in β-cells have minimal effects on function and islet transplant outcomes.

The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation.

Profilin-1 haploinsufficiency protects against obesity-associated glucose intolerance and preserves adipose tissue immune homeostasis.

Metabolic inflammation may contribute to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease. Previously, we showed that the actin-binding protein profilin-1 (pfn) plays a role in atherogenesis because pfn heterozygote mice (PfnHet) exhibited a significant reduction in atherosclerotic lesion burden and vascular inflammation. In the current study, we tested whether pfn haploinsufficiency would also limit diet-induced adipose tissue inflammation and insulin resistance (IR).

Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial.

Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM).

Objective: To assess 1-year efficacy and safety of salsalate in T2DM.

Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment.

A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance.

Aims/hypothesis: Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.

Retinal not systemic oxidative and inflammatory stress correlated with VEGF expression in rodent models of insulin resistance and diabetes.

Purpose: To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes.

Methods: Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers.

Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets.

Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation.

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation.

Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways.