GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice

The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders.     

Relationship Between Peer Victimization and Posttraumatic Stress Among Primary School Children

Peer victimization is a common stressor experienced by children. Although peer victimization has been studied extensively, few studies have examined the potential link between peer victimization and posttraumatic stress disorder (PTSD), and no studies of which we are aware have examined this link among children in primary school. The paucity of studies examining the link between PTSD and peer victimization in primary school is surprising because peer victimization occurs more frequently and is more likely to be physical among 7‐ and 8‐year‐old children. This study assessed the relationship between peer victimization and PTSD in a sample of 358 elementary school children (ages 6–11 years). Results indicated that peer victimization accounted for 14.1% of PTSD symptom severity among boys and 10.1% among girls. Additionally, we found gender differences in the types of peer victimization that were most associated with PTSD symptom severity (d = 0.38). The long‐term developmental consequences that may be associated with peer victimization‐linked PTSD symptomatology are discussed.     

Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples

Association genome scanning is of increasing interest for identifying the chromosomal regions that contain gene variants that contribute to vulnerability to complex disorders, including addictions. To improve the power and feasibility of this approach, we have validated "10k" microarray-based allelic frequency assessments in pooled DNA samples and have used this approach to seek allelic frequency differences between heavy poly-substance abusers and well characterized control individuals. Thirty-eight loci contain SNPs that display robust allele frequency differences between abusers and controls in both European- and African-American samples. These loci identify an alcohol/acetaldehyde dehydrogenase gene cluster and genes implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with previous linkage and association results for addictions. Pooled association genome scanning provides a useful tool for elucidating molecular genetic underpinnings of complex disorders and identifies both previously understood and previously unanticipated mechanisms for addiction vulnerability.     

Hepcidin,a putative mediator of anemia of inflammation,is a type II acute-phase protein

Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha (TNF-alpha), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation.     

Hepcidin--a regulator of intestinal iron absorption and iron recycling by macrophages

Hepcidin is a recently discovered peptide made in the liver, distributed in plasma and excreted in urine. This peptide hormone is the homeostatic regulator of intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting the efflux of iron through ferroportin, the sole known iron exporter of enterocytes, macrophages and hepatocytes. As befits an iron-regulatory hormone, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Hepcidin is markedly induced during infections and inflammation, causing iron to be sequestered in macrophages, hepatocytes and enterocytes. The resulting decrease in plasma iron levels eventually contributes to the anemia associated with infection and inflammation. These alterations in iron metabolism probably have a role in host defense by limiting the availability of iron to invading microorganisms. At the opposite extreme, early studies indicate that hepcidin deficiency--due to the dysregulation of its synthesis or mutations in the hepcidin gene itself--is the immediate cause of most forms of hemochromatosis.     

The effect of educational level on the incidence of asthma and respiratory symptoms

Few studies have examined the impact of socioeconomic status on the incidence of asthma and respiratory symptoms. Between 1985 and 1996/97, we conducted an 11-years community cohort study with 2819 subjects, aged 15-70 years at baseline, in Western Norway. We examined the cumulative incidence of asthma and respiratory symptoms by educational level (primary, secondary, and university), as well as estimating the odds ratios (ORs) of educational level on the incidences, after adjustment for sex, age, hay fever, smoking habits, pack years, and occupational exposure. For all respiratory symptoms, the incidences decreased with increasing educational level. The cumulative incidence of asthma was 5.3%, 4.1%, and 1.8%, respectively, for those with a primary educational level, secondary educational level, and university level. Subjects with a primary educational level had adjusted ORs (95% CI) from 1.4 (0.9, 2.3) for the incidence of chronic cough to 2.5 (1.6, 4.0) for the incidence of dyspnea grade 2, compared to those with a university level education. The adjusted OR (95% CI) for the incidence of asthma was 2.1 (1.01, 4.4) in subjects with a primary educational level, and 2.0 (1.04, 3.6) in subjects with a secondary educational level, compared to subjects with a university educational level. In conclusion, subjects with a lower educational level had a higher risk of developing asthma and respiratory symptoms, after adjustment for sex, age, hay fever, smoking, and occupational exposure.