Hypoxia responses in arginase 2 deficient mice enhance cardiovascular health.

Rationale: Physiological responses to hypoxia involve adaptations in the hematopoietic and cardiovascular systems, which work together to ensure adequate oxygen delivery to tissues for energy production. The arginine/nitric oxide (NO) pathway regulates both systems through its effects on erythropoiesis and vasodilation. In Tibetan populations native to high-altitude hypoxia, increased NO production from arginine and decreased arginine metabolism by arginase contribute to these adaptive mechanisms.

Creeping Fat-Derived Free Fatty Acids Induce Hyperplasia of Intestinal Muscularis Propria Muscle Cells: A Novel Link Between Fat and Intestinal Stricture Formation in Crohn's Disease.

Background & Aims: In Crohn's disease, wrapping of mesenteric fat around the bowel wall, so-called "creeping fat," is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We investigated creeping fat-derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia.

Blood Cholesterol and Triglycerides Associate with Right Ventricular Function in Pulmonary Hypertension.

Background: Blood lipids are dysregulated in pulmonary hypertension (PH). Lower high-density lipoproteins cholesterol (HDL-C) and low-density lipoproteins cholesterol (LDL-C) are associated with disease severity and death in PH. Right ventricle (RV) dysfunction and failure are the major determinants of morbidity and mortality in PH.

Method for depletion of mitochondria DNA in human bronchial epithelial cells.

Mitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines that are depleted of mitochondrial DNA.

Method for Depletion of Mitochondria DNA in Human Bronchial Epithelial Cells.

Introduction: Mitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines derived from primary airway epithelium that are depleted of mitochondrial DNA.

GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.

Unlabelled: Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We used electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned medium enhanced glucose-stimulated insulin secretion (GSIS).

Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.

Background And Aims: A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial.

Methods: 19 healthy adults (age:28.

Resting Energy Expenditure Is Elevated in Asthma.

Asthma physiology affects respiratory function and inflammation, factors that may contribute to elevated resting energy expenditure (REE) and altered body composition. We hypothesized that asthma would present with elevated REE compared to weight-matched healthy controls. Adults with asthma ( = 41) and healthy controls ( = 20) underwent indirect calorimetry to measure REE, dual-energy X-ray absorptiometry (DEXA) to measure body composition, and 3-day diet records.

Roux-en-Y gastric bypass restores islet function and morphology independent of body weight in ZDF rats.

Reductions in β-cell number and function contribute to the onset type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery can resolve T2D within days of operation, indicating a weight-independent mechanism of glycemic control. We hypothesized that RYGB normalizes glucose homeostasis by restoring β-cell structure and function.

Metabolic effects of duodenojejunal bypass surgery in a rat model of type 1 diabetes.

Background: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis.

Methods: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n = 15) or sham (n = 15) surgery at a median age of 41 days, before development of diabetes.

BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control.

Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis.

Effects of gastric bypass surgery on expression of glucose transporters and fibrotic biomarkers in kidney of diabetic fatty rats.

Background: Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy.

Objectives: To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy.

Exercise training remodels human skeletal muscle mitochondrial fission and fusion machinery towards a pro-elongation phenotype.

Aims: Mitochondria exist as a morphologically plastic network driven by cellular bioenergetic demand. Induction of fusion and fission machinery allows the organelle to regulate quality control and substrate flux. Physiological stressors promote fragmentation of the mitochondrial network, a process implicated in the onset of metabolic disease, including type 2 diabetes and obesity.

Mitochondrial dynamics in skeletal muscle insulin resistance and type 2 diabetes.

The traditional view of mitochondria as isolated, spherical, energy producing organelles, is undergoing a revolutionary change. Emerging data show that mitochondria form a dynamic reticulum that is regulated by cycles of fission and fusion. The discovery of proteins that modulate these activities has led to important advances in understanding human disease.

2-Octylcyanoacrylate for the prevention of anastomotic leak.

Background: Anastomotic leak after colorectal surgery is a significant cause of morbidity and mortality. The aim of this study was to evaluate the impact of a reinforced colo-colonic anastomosis with tissue adhesive, 2-octylcyanoacrylate (2-OCA), on the integrity of anastomotic healing as measured by anastomotic bursting pressure.

Methods: Sixty-eight female Sprague-Dawley rats underwent a rectosigmoid colon transection and a sutured end-to-end anastomosis followed by randomization to receive no further intervention or reinforcement with the tissue adhesive, 2-OCA.

Effect of Roux-en-Y gastric bypass on liver mitochondrial dynamics in a rat model of obesity.

Bariatric surgery provides significant and durable improvements in glycemic control and hepatic steatosis, but the underlying mechanisms that drive improvements in these metabolic parameters remain to be fully elucidated. Recently, alterations in mitochondrial morphology have shown a direct link to nutrient adaptations in obesity. Here, we evaluate the effects of Roux-en-Y gastric bypass (RYGB) surgery on markers of liver mitochondrial dynamics in a diet-induced obesity Sprague-Dawley (SD) rat model.

In vitro contraction protects against palmitate-induced insulin resistance in C2C12 myotubes.

We are interested in understanding mechanisms that govern the protective role of exercise against lipid-induced insulin resistance, a key driver of type 2 diabetes. In this context, cell culture models provide a level of abstraction that aid in our understanding of cellular physiology. Here we describe the development of an in vitro myotube contraction system that provides this protective effect, and which we have harnessed to investigate lipid-induced insulin resistance.

Exercise training-induced improvement in skeletal muscle PGC-1α-mediated fat metabolism is independent of dietary glycemic index.

Objective: This study hypothesized that a low-glycemic diet combined with exercise would increase expression of nuclear regulators of fat transport and oxidation in insulin-resistant skeletal muscle.

Method: Nineteen subjects (64 ± 1 y; 34 ± 1 kg/m ) were randomized to receive isocaloric high-glycemic-index (HiGIX; 80 ± 0.6 units, n = 10) or low-glycemic-index (LoGIX; 40 ± 0.

Effect of Roux-en-Y Gastric Bypass on the NLRP3 Inflammasome in Pancreatic Islets from Zucker Diabetic Fatty Rats.

Purpose: Diabetes and obesity are associated with inflammasome-mediated low-grade, chronic inflammation that may induce pancreatic beta-cell dysfunction and apoptosis. We examined the effects of Roux-en-Y gastric bypass (RYGB) surgery on NOD-like receptor family, pyrin domain containing-3 (NLRP3) inflammasome-related genes from pancreatic islets of Zucker diabetic fatty rats.

Materials And Methods: Islets were collected from Zucker diabetic fatty sham control and RYGB, 30 days after surgery.

Brown and Beige Adipose Tissue: Therapy for Obesity and Its Comorbidities?

Overweight and obesity are global health problems placing an ever-increasing demand on health care systems. Brown adipose tissue (BAT) is present in significant amounts in adults. BAT has potential as a fuel for oxidation and dissipation as heat production, which makes it an attractive target for obesity therapy.

Effect of Roux-en-Y Gastric Bypass on the NLRP3 Inflammasome in Adipose Tissue from Obese Rats.

Objective: Obesity is associated with low-grade chronic inflammation. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery would reduce activation of the NLRP3 inflammasome in metabolically active adipose tissue (AT) of obese rats, and this change would be related to decreases in body weight and improved glycemic control.

Methods: Omental, mesenteric and subcutaneous fat depots were collected from Sprague-Dawley rats: Sham control and RYGB; 90-days after surgery.

Microparticles release by adipocytes act as "find-me" signals to promote macrophage migration.

Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical "find-me" signals for recruitment of monocytes and macrophages.

Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle.

Defects in mitochondrial dynamics, the processes of fission, fusion, and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser(616) phosphorylation and increase fat oxidation and insulin sensitivity in obese (body mass index: 34.

Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice.

Background & Aims: Activation of Fas death receptor results in apoptosis in multiple organs, particularly liver, in a process dependent on Bid cleavage. Mice injected with an anti-Fas antibody die within hours of acute liver failure associated with massive apoptosis and hemorrhage. Our aim was to investigate the crosstalk of apoptotic and inflammatory pathways and the contribution of selective hepatocellular apoptosis during in vivo Fas activation.

Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells.

Angiogenesis is a key pathological feature of experimental and human steatohepatitis, a common chronic liver disease that is associated with obesity. We demonstrated that hepatocytes generated a type of membrane-bound vesicle, microparticles, in response to conditions that mimicked the lipid accumulation that occurs in the liver in some forms of steatohepatitis and that these microparticles promoted angiogenesis. When applied to an endothelial cell line, medium conditioned by murine hepatocytes or a human hepatocyte cell line exposed to saturated free fatty acids induced migration and tube formation, two processes required for angiogenesis.