Direct Control of Brown Adipose Tissue Thermogenesis by Central Nervous System Glucagon-Like Peptide-1 Receptor Signaling

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)–deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1rp>−/−p> mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.The increasing incidence of type 2 diabetes (T2D) and obesity worldwide has prompted the need for new therapies. Agonism of the receptor for glucagon-like peptide-1 (GLP-1) is currently one of the most successfully and widely used therapies for T2D. GLP-1 is a product of proglucagon that also gives rise to glucagon (GCG) and oxyntomodulin (OXM) (1). Both GLP-1 and its receptor (GLP-1R) are expressed in peripheral tissues and in areas of the central nervous system (CNS) involved in the control of energy balance. Treatment with GLP-1R agonists improves glycemic control and reduces body weight in diabetic humans (2). Studies in animals have demonstrated that CNS–GLP-1R signaling contributes to the body weight–reducing effect of these agonists (3).GCG is produced in the α cells of the pancreatic islets and is involved in the maintenance of euglycemia. Although its exogenous administration induces body weight loss associated with anorexia and increased energy expenditure (4), GCG has been traditionally dismissed as a potential drug target because of its diabetogenic effects. However, recent preclinical data have shown that simultaneous activation of both GLP-1R and GCG receptor (GCGR) leads to greater efficacy in both glycemic control and weight loss than the activation of GLP-1R alone (5,6).OXM can bind to and activate both GLP-1R and GCGR (7), and studies with rodents (8,9) and humans (10) suggest that it may be efficacious in treating obesity and diabetes. OXM regulates feeding, at least in part, through GLP-1R (7,11). There is evidence that OXM action in the CNS reduces body weight by increasing energy expenditure (12). This may involve activation of brown adipose tissue (BAT) metabolism, since intracerebroventricular (ICV) administration of OXM reduces the weight of interscapular BAT (iBAT) pads and increases body temperature in rats (12). The relative contribution of GLP-1R and GCGR to this process has never been investigated; however, it is known that GCG regulates iBAT activity, and this may be, at least in part, centrally mediated (13). The contribution of GLP-1R to the control of energy expenditure, and more specifically to BAT metabolism, remains largely unknown.The sympathetic nervous system (SNS) is essential for control of BAT metabolism by the CNS (14) and is involved in the CNS–GLP-1R control of lipid metabolism in white adipose tissue (WAT) (15). This, in addition to the evidence that GCG may increase BAT thermogenesis through actions in the CNS (13), led us to hypothesize that the action(s) of GCGR and GLP-1R in the brain controls BAT thermogenesis through the SNS. Here, we show that central administration of both GCGR and GLP-1R agonists increased SNS activity to iBAT and induced thermogenesis. Thus, we propose that CNS–GLP-1R may contribute to the control of energy balance by regulating BAT thermogenesis. The existence of functional BAT in adult humans has now been determined (16–18), and effort needs to be directed toward a better understanding of the regulation of this tissue as a target for antiobesity therapeutics. The increase in BAT metabolism described here may contribute to the weight loss induced by GCGR and GLP-1R agonists in both animal models and humans.     

Ventral hernia repair: a study of current practice

Ventral wall hernias are common; despite this, there are no guidelines on the best surgical management. The aim of this study was to examine the types of repair in use for abdominal wall hernias in the West of Scotland over a 3-month period. Data were gathered on 120 patients. There were 60 incisional, 32 umbilical, and 28 epigastric hernias. The main indication for repair was pain (78%), while 12 patients (10%), presented acutely with incarceration or strangulation. The most common method of repair was sutured (55%), followed by mesh (29%) and Mayo repair (16%). There was no correlation between use of mesh and hernia size or whether repair was for a recurrent hernia. Surgical practice varies widely in the repair of ventral wall hernias. Clinical trials are required to establish the best method of repair for this common condition. Electronic Publication     

T cell lymphoplasmacellular and eosinophilic infiltration of the pancreas with involvement of the gallbladder and duodenum in non-alcoholic duct-destructive chronic pancreatitis

Background Non-alcoholic duct destructive chronic pancreatitis is a rare entity with specific pathological features. The majority of the patients are from Japan. We report a case with involvement of the distal bile duct, the gallbladder, the duodenum and the ampulla, and present a review of patients from Europe and the USA since 1997.Case presentation A 56-year-old man presented with a 3-month history of mild acute pancreatitis and obstructive jaundice, followed by increasing weight loss, lethargy and epigastric pain. CT showed a mass in the head of the pancreas. ERCP demonstrated a smooth stricture of the intra-pancreatic main bile duct and an irregular, incomplete, stricture in the main pancreatic duct. A pancreatic cancer could not be reliably excluded, and, therefore, he underwent a pylorus-preserving Kausch–Whipples pancreatoduodenectomy.Results Histopathology showed typical peri-ductal T cell-rich lymphoplasmacellular and eosinophilic infiltration of the pancreas, with involvement of the distal bile duct but, also, unusual inflammatory infiltration of the gallbladder, the duodenum and the ampulla.Conclusion The inflammatory process in non-alcoholic duct-destructive chronic pancreatitis can affect the entire pancreato-biliary region and mimics pancreatic cancer. Currently, there are no definitive criteria for pre-operative diagnosis, so it is very difficult for one to avoid resection.     

The pathogenesis of nasal polyposis by immunoglobulin E and interleukin-5 is completed by transforming growth factor-beta1

OBJECTIVES/HYPOTHESIS: Nasal polyps are benign mucosal protrusions into the nasal cavity of multifactorial origin and are characterized by chronic mucosal inflammation. The suggested multifactorial pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was designed to examine the suggested roles of IgE, interleukin-5 (IL-5), and transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of nasal polyposis. METHODS: Nasal polyps (n = 34) and healthy nasal mucosa samples (n = 9) were taken during routine endonasal surgeries. Immunoglobulin E (n = 13), IL-5 (n = 22), and TGF-beta1 (n = 27) concentrations were measured with enzyme-linked immunosorbent assay technique in homogenized polyp tissue and in control mucosa. Atopic and nonatopic groups were selected and compared. Histomorphological examination and immunohistochemical analysis to detect IL-5 and TGF-beta1 were performed in five specimens. RESULTS: The level of tissue-bound IgE was significantly higher in polyps compared with control specimens and in atopic compared with nonatopic polyps, but between nonatopic polyps and control specimens the difference was not significant. However, significant correlation was found between tissue and serum IgE in the complete polyp (P =.001) and atopic polyps group (P =.05). Tissue IL-5 concentration was significantly higher in polyps compared with control specimens, in which it was below the limit (15 pg/mL), and there was no difference between atopic and nonatopic polyps. In atopic polyps there was significant correlation between tissue IgE and IL-5. Transforming growth factor-beta1 concentration proved to be significantly higher in control mucosa than in polyps, with no difference between atopic and nonatopic polyps. Immunohistochemical analysis revealed numerous IL-5-positive eosinophil cells and TGF-beta1 positivity in the lamina propria of polyp samples, but none in control specimens. CONCLUSIONS: High tissue TGF-beta1 quantity in healthy nasal mucosa without its active form on the cell surface and its low quantity in polyps may reflect its essential role in the inhibitory mechanisms of nasal polyposis. Interleukin-5 plays a key role in the eosinophil recruitment and activation, and both atopic and nonatopic pathways might activate this process. The main sources of IL-5 and TGF-beta1 are the eosinophils and macrophages. Immediate hypersensitivity, besides other mechanisms, might be related to atopic polyps, but the involvement of other, local allergic mechanisms in IgE production of nonatopic polyp tissue cannot be excluded.     

Mauricio Goihman-Yahr, MD, PhD, Editor

The Correspondence Section serves as a forum for opinion exchange about subjects of general interest such as dermatoiogic training, relations between dermatologists and pharmaceutical houses, governmental control of dermatology and medical practice in general, peculiarities of dermatology related to geographic, climatic, or racial factors, the flow of information and publications, as well as other concerns the readership might have. Contributions are welcome and should conform to the usual format for correspondence. Manuscripts will undergo standard editorial procedures. Submit all correspondence to Mauricio Goihman-Yahr, md,p h d , Editor, Jet International M-154, PO Box 020010, Miami, FL 33102.     

Maternal serum thrombospondin-1 is significantly altered in cases with established preeclampsia

Purpose: The aim of the study was to investigate whether maternal serum TSP-1 level was associated with PE.p>Materials and methods: In our case control study, 84 pregnant women in the third trimester were included. Forty-one of them were healthy and 43 of them were with the diagnosis of PE. The diagnosis was based on the definitions of the National High Blood Pressure Education Program working Group on High Blood Pressure in Pregnancy. Preeclamptic patients were divided into two subgroups as mild and severe. Blood pressure (BP) of pregnant women were obtained in left-side lying position using a mercury sphygmomanometer after at least 10 minutes of rest. Ten milliliters of venous blood was taken from every pregnant women and dispensed into lithium heparin and serum was obtained. Samples were stored at ?80?°C until analyzed. Serum TSP-1 level was measured using enzyme-linked immunosorbent assay (ELISA). All tests were two-tailed and p < .05 was considered to be statistically significant.p>Results: TSP-1 level was significantly lower in PE group than in controls (p?=?.003). Platelet counts were similar in two groups (p = .26). TSP-1 levels were significantly lower in severe PE than in mild PE cases. According to the subgroup analysis, TSP-1 level was found significantly lower in severe preeclampsia group compared to control group (p = .015).p>Conclusions: In light of the association between endothelial dysfunction and preeclampsia, we claim that lower levels of TSP-1 which is released mostly from endothelial cells seem to reflect disease severity in PE. Our study reveals that maternal serum TSP-1 levels decrease in pregnant women presenting with PE and TSP-1 may be a new biomarker for the detection of PE and even severity of it. Further studies especially prospective ones with greater numbers of cases are needed.     

Decreased frequency of HLA-B35 in patients with gastric MALT lymphoma

Persistent infection with Helicobacter pylori has been shown to be strongly associated with the development of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the prevalence of H. pylori infection exceeds the incidence of MALT lymphoma by far. This discrepancy might at least partially be explained on a genomic basis of the host. To evaluate the association between HLA type and MALT lymphoma, we investigated 46 patients with MALT lymphoma recruited in a prospective multicenter study from October 1998 to March 2001. Over 13,000 voluntary stem cell donors from over 40 German blood banks represented the control group. Exploratory statistical analysis using Fishers exact test showed significantly decreased frequency of HLA-B35 in the MALT lymphoma group compared to the control group. Our data suggest a negative association between HLA-B35 and MALT lymphoma; however, larger studies are necessary to confirm a protective role of this HLA antigen.