Search

OBJECTIVE Circulating markers of iron overload are associated with insulin resistance. Less is known about the impact of iron overload on adipose tissue (AT). We hypothesized that gene expression markers [...]

Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesity-related inflammation and insulin resistance, we compared wild-type and [Itch.sup.-/-] mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, [Itch.sup.-/-] mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from [Itch.sup.-/-] mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity. Diabetes 2014;63:514-525 | DOI: 10.2337/db13-0802, Obesity is associated with a chronic state of low-grade inflammation, which predisposes to insulin resistance, type 2 diabetes, hepatic steatosis, and atherosclerosis (1-4). Obesity is also characterized by a progressive [...]

Retinoblastoma (Rb1) has been described as an essential player in white adipocyte differentiation in mice. No studies have been reported thus far in human adipose tissue or human adipocytes. We aimed to investigate the possible role and regulation of RB1 in adipose tissue in obesity using human samples and animal and cell models. Adipose RB1 (mRNA, protein, and activity) was negatively associated with BMI and insulin resistance (HOMA-IR) while positively associated with the expression of adipogenic genes (PPARγ and IRS1) in both visceral and subcutaneous human adipose tissue. BMI increase was the main contributor to adipose RB1 downregulation. In rats, adipose Rb1 gene expression and activity decreased in parallel to dietary-induced weight gain and returned to baseline with weight loss. RB1 gene and protein expression and activity increased significantly during human adipocyte differentiation. In fully differentiated adipocytes, transient knockdown of Rb1 led to loss of the adipogenic phenotype. In conclusion, Rb1 seems to play a permissive role for human adipose tissue function, being downregulated in obesity and increased during differentiation of human adipocytes. Rb1 knockdown findings further implicate Rb1 as necessary for maintenance of adipogenic characteristics in fully differentiated adipocytes., Adipose tissue plays a central role in the management of systemic energy storage as well as in many other processes. This is due to its capacity to store triglycerides and [...]

GPR55 is a putative cannabinoid receptor, and L-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenlc genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans. Diabetes 61:281-291, 2012, In addition to their ability to store triacylglycerol, adipocytes act as endocrine secretory cells (1). A growing number of adipocyte-derived factors have been described, and their contribution to the pathophysiology [...]

OBJECTIVE--The study objective was to evaluate the possible role of the macrophage molecule CD14 in insulin resistance. RESEARCH DESIGN AND METHODS--The effects of recombinant human soluble CD14 (rh-sCD14) on insulin sensitivity (clamp procedure) and adipose tissue gene expression were evaluated in wild-type (WT) mice, high fat-fed mice, ob/ob mice, and CD14 knockout (KO) mice. We also studied WT mice grafted with bone marrow stem cells from WT donor mice and CD14 KO mice. Finally, CD14 was evaluated in human adipose tissue and during differentiation of human preadipocytes. RESULTS--rh-sCD14 led to increased insulin action in WT mice, high-fat-fed mice, and ob/ob mice, but not in CD14 KO mice, in parallel to a marked change in the expression of 3,479 genes in adipose tissue. The changes in gene families related to lipid metabolism were most remarkable. WT mice grafted with bone marrow stem cells from WT donor mice became insulin resistant after a high-fat diet. Conversely, WT mice grafted with cells from CD14 KO mice resisted the occurrence of insulin resistance in parallel to decreased mesenteric adipose tissue inflammatory gene expression. Glucose intolerance did not women in CD14 KO mice grafted with bone marrow stem cells from high fat-fed WT mice when compared with recipient KO mice grafted with cells from CD14 KO donor mice. CD14 gene expression was increased in whole adipose tissue and adipocytes from obese humans and further increased after tumor necrosis factor-α. CONCLUSIONS--CD14 modulates adipose tissue inflammatory activity and insulin resistance., Insulin resistance and chronic, low-grade inflammation are important predisposing factors for the development of type 2 diabetes and atherosclerosis. Genes and environment unequivocally induce variations in the inflammatory response that [...]

Obesity is well known to be associated with a cluster of metabolic diseases such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Alterations of the innate immune [...]

OBJECTIVE--Metformin has been well characterized in vitro as a substrate of liver-expressed organic cation transporters (OCTs). We investigated the gene expression and protein levels of OCT-1 and OCT-2 in adipose tissue and during adipogenesis and evaluated their possible role in metformin action on adipocytes. RESEARCH DESIGN AND METHODS--OCT1 and OCT2 gene expressions were analyzed in 118 adipose tissue samples (57 visceral and 61 subcutaneous depots) and during human preadipocyte differentiation. To test the possible role of OCT1 mediating the response of adipocytes to metformin, cotreatments with cimetidine (OCT blocker, 0.5 and 5 mmol/l) and metformin were made on human preadipocytes and subcutaneous adipose tissue (SAT). RESULTS--OCT1 gene was expressed in both subcutaneous and visceral adipose tissue. In both fat depots, OCT1 gene expression and protein levels were significantly increased in obese subjects. OCT1 gene expression in isolated preadipocytes significantly increased during differentiation in parallel to adipogenic genes. Metformin (5 mmol/l) decreased the expression of lipogenic genes and lipid droplets accumulation while increasing AMP-activated protein kinase (AMPK) activation, preventing differentiation of human preadipocytes. Cotreatment with cimetidine restored adipogenesis. Furthermore, metformin decreased IL-6 and MCP-1 gene expression in comparison with differentiated adipocytes. Metformin (0.1 and 1 mmol/l) decreased adipogenic and inflammatory genes in SAT. OCT2 gene expression was not detected in adipose tissue and was very small in isolated preadipocytes, disappearing during adipogenesis. CONCLUSIONS--OCT1 gene expression and protein levels are detectable in adipose tissue. Increased OCT1 gene expression in adipose tissue of obese subjects might contribute to increased metformin action in these subjects. Diabetes 60:168-176, 2011, Metformin (dimethylbiguanidine) is the most widely used drug for the treatment of type 2 diabetes (1,2). This insulin-sensitizing agent has well known beneficial effects not only on glycemic control, but [...]

CONTEXT--Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases. The aim of this study was to determine whether circulating FASN could be a biomarker of overnutrition-induced metabolic stress and insulin resistance in common metabolic disorders. RESEARCH DESIGN AND METHODS--Circulating FASN was evaluated in two cross-sectional studies in association with insulin sensitivity and in four longitudinal studies investigating the effect of diet- and surgery-induced weight loss, physical training, and adipose tissue expansion using peroxisome proliferator-activated receptor agonist rosiglitazone on circulating FASN. RESULTS--Age- and BMI-adjusted FASN concentrations were significantly increased in association with obesity-induced insulin resistance in two independent cohorts. Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P = -0.63; P < 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN. Improved insulin sensitivity induced by therapeutic strategies that decreased fat mass (diet induced, surgery induced, or physical training) all led to decreased FASN levels in blood (P values between 0.02 and 0.04). To discriminate whether this was an effect related to insulin sensitization, we also investigated the effects of rosiglitazone. Rosiglitazone did not lead to significant changes in circulating FASN concentration. CONCLUSIONS--Our results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress., The main problem of obesity is not as much the degree of expansion of the adipose tissue as the increased susceptibility to cardiometabolic risk. As obesity becomes more prevalent, a [...]

OBJECTIVE--Activation of the alternative pathway of the complement system, in which factor II (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS--Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS--Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS--Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances., Obesity is closely associated with a cluster of metabolic diseases, such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Adipose tissue is well known for its essential [...]

Backgrounds The hospital admission and mortality rates of patients with diabetic emergencies, such as diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS), are higher in black patients than in white patients with diabetes. However, there is limited data describing the precipitating events and response to treatment in black patients. Analysis of their clinical characteristics and response to medical therapy is needed to evaluate the impact of programs designed to reduce the development of these acute metabolic complications. Methods: A prospective evaluation was conducted of 144 consecutive patients with DKA and 23 patients with HHNS admitted to a large inner-city hospital between July 1993 and October 1994. Results: In patients previously diagnosed as having diabetes, poor compliance with insulin therapy was the major precipitating cause for DKA (49%) and HHNS (42%). Alcohol or cocaine abuse was a contributing factor for noncompliance and was present in 35% and 13% of patients with DKA and in 44% and 9% of patients with HHNS, respectively. Newly diagnosed diabetes accounted for 17% of patients with DKA and HHNS. Obesity (body mass index [is greater than] 28 kg/[m.sub.2] [the weight in kilograms divided by the square of the height in meters]) was present in 29% of patients with DKA and in 17% with HHNS and was most common in patients with DKA who were newly diagnosed as having diabetes (56%). Patients were treated by residents, who used a low-dose insulin protocol with an algorithm for insulin adjustment in 88 of 144 patients with DKA and 14 of 23 patients with HHNS. Although there was no difference in mortality rates or time needed to correct hyperglycemia or ketoacidosis, the use of the protocol significantly reduced the risk of hypoglycemia (5%) compared with patients treated without a protocol (23%) (P[is less than] .01). Conclusions: In urban black patients, poor compliance with insulin therapy was the main precipitating cause of acute metabolic decompensation, and substance abuse was a significant contributing factor for noncompliance. Obesity is common in black patients with DKA; it was present in more than half of those with newly diagnosed diabetes. Improved patient education and better access to medical care might reduce the development of these hyperglycemic emergencies.

Supplemental Digital Content is available in the text.

Retrospective study to examine the outcomes of acute kidney injury requiring dialysis (AKI-D) patients that received outpatient hemodialysis as part of continued AKI-D care and explore factors associated with recovery of kidney function and discontinuation of dialysis.

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5–9and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10–13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.

Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5bproximal promoter and represses its expression. Silencing of Cox5bdecreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5bsilencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5Bgene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion.

This paper aims at designing optimal gear shift strategies for conventional passenger vehicles equipped with discrete ratio transmissions. In order to study quantitatively an optimal trade-off between the fuel economy and the driveability, the vehicle driveability is addressed in a fuel-optimal gear shift algorithm based on dynamic programming by three methods: method 1, weighted inverse of power reserve; method 2, constant power reserve; method 3, variable power reserve. Furthermore, another method based on stochastic dynamic programming is proposed to derive an optimal gear shift strategy over a number of driving cycles in an average sense, hence taking into account the vehicle driveability. In contrast with the dynamic-programming-based strategy, the obtained gear shift strategy based on stochastic dynamic programming is real time implementable. A comparative analysis of all proposed gear shift methods is given in terms of the improvements in the fuel economy and the driveability. The variable-power-reserve method achieves the highest fuel economy without sacrificing the driveability.

Sickle cell disease causes several kidney manifestations. They include defects in urine concentration, impaired handling of potassium and hydrogen ion, albuminuria, acute kidney injury, and chronic kidney disease to name a few. Glomerular hyperfiltration, tubular hyperfunctioning, endothelial damage from repeated sickling and vaso-occlusive episodes, and iron-induced proinflammatory changes in the glomerular mesangium and tubulointerstitium are some of the mechanisms of kidney damage. Albuminuria is one of the most and common clinical features of kidney disease and progresses with age. Kidney disease in patients with sickle cell is associated with increased mortality. Annual screening for proteinuria starting at age 10 years and limiting the use of nonsteroidal anti-inflammatory agents and the use of angiotensin-converting enzyme inhibitors may help in early detection and delaying the progression of kidney disease. Adequate hydration, angiotensin-converting enzyme inhibitors, and adequate control of sickle cell are the main stay of treatment for albuminuria. The hemoglobin goal for patients with sickle cell nephropathy is lesser (10 g/dL) than that for patients with chronic kidney disease due to other causes given that a higher hemoglobin level increases viscosity and the risk of precipitating vaso-occlusive episodes. A multidisciplinary approach is recommended for managing patients with sickle cell and kidney diseases.

Navarrete x Kajiyama Dance Theater creates interdisciplinary performance works using movement, theater, art installation, and site-specific environments. Our work has been influenced by ritual, cultural studies, and the political and environmental concerns of the world in which we live.