Cellular Plasticity of Defa4-Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury.

Background & Aims: Loss of leucine-rich repeat-containing G-protein-coupled receptor 5-positive crypt base columnar cells provides permissive conditions for different facultative stem cell populations to dedifferentiate and repopulate the stem cell compartment. In this study, we used a defensin α4-Cre recombinase (Defa4Cre) line to define the potential of Paneth cells to dedifferentiate and contribute to intestinal stem cell (ISC) maintenance during normal homeostasis and after intestinal injury.

Methods: Small intestine and enteroids from Defa4;Rosa26 tandem dimer Tomato (tdTomato), a red fluoresent protein, (or Rosa26 Enhanced Yellow Fluorescent Protein (EYFP)) reporter, Notch gain-of-function (Defa4;Rosa26 Notch Intracellular Domain (NICD)-ires-nuclear Green Fluorescent Protein (nGFP) and Defa4;Rosa26 Enhanced Green Fluorescent Protein (EGFP);TetO), A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) loss-of-function (Defa4;ADAM10), and Adenomatous polyposis coli (APC) inactivation (Defa4;APC) mice were analyzed.

Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn's disease.

It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome.

Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation.

The protozoan parasite Toxoplasma gondii triggers severe small intestinal immunopathology characterized by IFN-γ- and intestinal microbiota-mediated inflammation, Paneth cell loss, and bacterial dysbiosis. Paneth cells are a prominent secretory epithelial cell type that resides at the base of intestinal crypts and releases antimicrobial peptides. We demonstrate that the microbiota triggers basal Paneth cell-specific autophagy via induction of IFN-γ, a known trigger of autophagy, to maintain intestinal homeostasis.

Therapeutic Endoscopy for the Control of Nonvariceal Upper Gastrointestinal Bleeding in Children: A Case Series.

Objectives: Gastrointestinal bleeding is one of the most common indications for urgent endoscopy in the pediatric setting. The majority of these procedures are performed for control of variceal bleeding, with few performed for nonvariceal upper gastrointestinal (NVUGI) bleeding. The data on therapeutic endoscopy for NVUGI are sparse.

Tips and Tricks on How to Optimally Manage Patients with Upper Gastrointestinal Bleeding.

Effective endoscopic therapy for upper gastrointestinal (GI) bleeding has been shown to reduce rebleeding, need for surgery, and mortality. Effective endoscopic management of acute upper GI bleeding can be challenging and worrying. This article provides advice that is complementary to the in-depth reviews that accompany it in this issue.

Leptin acts independently of food intake to modulate gut microbial composition in male mice.

Shifts in the composition of gut bacterial populations can alter host metabolism and may contribute to the pathogenesis of metabolic disorders, including obesity. Mice deficient in leptin action are obese with altered microbiota and increased susceptibility to certain intestinal pathogens. Because antimicrobial peptides (AMPs) secreted by Paneth cells represent a major mechanism by which the host influences the gut microbiome, we examined the mRNA expression of gut AMPs, several of which were decreased in leptin receptor (LepR)-deficient db/db mice, suggesting a potential role for AMP modulation of microbiota composition.

Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention.

Adiponectin is a secretory protein abundantly secreted from adipocytes. It assembles into a number of different higher-order complexes. Adipocytes maintain tight control over circulating plasma levels, suggesting the existence of a complex, highly regulated biosynthetic pathway.

Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists.

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model.

Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action.

The adipocytokine resistin impairs glucose tolerance and insulin sensitivity in rodents. Here, we examined the effect of resistin on glucose uptake in isolated adult mouse cardiomyocytes. Murine resistin reduced insulin-stimulated glucose uptake, establishing the heart as a resistin target tissue.

The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.

Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia.

Fat-cell mass, serum leptin and adiponectin changes during weight gain and loss in yellow-bellied marmots (Marmota flaviventris).

Leptin and adiponectin are proteins produced and secreted from white adipose tissue and are important regulators of energy balance and insulin sensitivity. Seasonal changes in leptin and adiponectin have not been investigated in mammalian hibernators in relationship to changes in fat cell and fat mass. We sought to determine the relationship between serum leptin and adiponectin levels with seasonal changes in lipid mass.

Optimization of protein production in mammalian cells with a coexpressed fluorescent marker.

The expression of mammalian proteins in sufficient abundance and quality for structural studies often presents formidable challenges. Many express poorly in bacterial systems, whereas it can be time consuming and expensive to produce them from cells of higher organisms. Here we describe a procedure for the direct selection of stable mammalian cell lines that express proteins of interest in high yield.

Role of resistin in diet-induced hepatic insulin resistance.

Resistin is an adipose-derived hormone postulated to link adiposity to insulin resistance. To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, we lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin-clamp technique. After 3 weeks on a high-fat (HF) diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels.

Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting.

Resistin was originally reported as an adipose tissue-specific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance.

Disulfide-dependent multimeric assembly of resistin family hormones.

Resistin, founding member of the resistin-like molecule (RELM) hormone family, is secreted selectively from adipocytes and induces liver-specific antagonism of insulin action, thus providing a potential molecular link between obesity and diabetes. Crystal structures of resistin and RELMbeta reveal an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich beta-sandwich "head" domain and an amino-terminal alpha-helical "tail" segment.

Regulation of fasted blood glucose by resistin.

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver.

Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates beta oxidation in muscle.

A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity.

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold.

Minireview: The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis.

Adipose tissue evolved to efficiently store energy for times of caloric restriction. The large caloric excess common in many Western diets has negated the need for this thrifty function, leaving adipose tissue ill-equipped to handle this increased load. An excess of adipose tissue increases risk for a number of conditions including coronary artery disease, hypertension, dyslipidemias, type 2 diabetes, and even cancer.

Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin.

Adiponectin or adipocyte complement-related protein of 30 kDa (Acrp30) is a circulating protein produced exclusively in adipocytes. Circulating Acrp30 levels have been associated with insulin sensitivity in adult mice and humans, yet the Acrp30 profile over the lifespan and its hormonal regulation in vivo have not been previously described. Hence, we set forth to determine whether hormonal and metabolic changes associated with sexual maturation, reproduction, aging, and calorie restriction affect Acrp30.

Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production.

The adipose-derived hormone resistin is postulated to link obesity to insulin resistance and diabetes. Here, the infusion of either resistin or the resistin-like molecule-beta (RELMbeta) rapidly induced severe hepatic but not peripheral insulin resistance. In the presence of physiologic hyperinsulinemia, the infusion of purified recombinant resistin, increasing circulating resistin levels by approximately twofold to 15-fold, inhibited glucose metabolism such that lower rates of glucose infusion were required to maintain the plasma glucose concentration at basal levels.

Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?

Age-dependent changes in insulin action and body fat distribution are risk factors for the development of type 2 diabetes. To examine whether the accumulation of visceral fat (VF) could play a direct role in the pathophysiology of insulin resistance and type 2 diabetes, we monitored insulin action, glucose tolerance, and the expression of adipo-derived peptides after surgical removal of VF in aging (20-month-old) F344/Brown Norway (FBN) and in Zucker Diabetic Fatty (ZDF) rats. As expected, peripheral and hepatic insulin action were markedly impaired in aging FBN rats, and extraction of VF (accounting for approximately 18% of their total body fat) was sufficient to restore peripheral and hepatic insulin action to the levels of young rats.