The emerging pattern of the genetic contribution to human obesity

It has been a little more than 5 years since the publication of the first genome scans focused on obesity-related phenotypes in humans. While the number of scans reported has grown steadily during this time, the results from many of these studies have been modest at best. However, there are a handful of studies that have now reported highly significant findings, and even more important perhaps is the fact that several of these findings have now been replicated as well. Currently there is strong statistical support for approximately half a dozen quantitative trait loci (QTLs) influencing obesity-related phenotypes across a number of populations and ethnic groups. While some of these signals localize near genes that might have been considered a priori as candidate genes for obesity, several others offer evidence for previously unsuspected genes. As a result, there is an intriguing pattern of genetic contribution to obesity that has begun to emerge and which promises to greatly increase our understanding of the relationship between obesity and other chronic diseases such as coronary heart disease and type 2 diabetes.     

Chronic Continuous Exenatide Infusion Does Not Cause Pancreatic Inflammation and Ductal Hyperplasia in Non-Human Primates

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67–positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67–positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67–positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30–positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-IV (DPP-IV) inhibitors represent new classes of therapeutic agents for type 2 diabetes mellitus treatment acting by augmenting β-cell function while decreasing food intake and body weight.^1–7Isolated cases of pancreatitis have been reported in diabetic patients treated with GLP-1 receptor agonists and DPP-IV inhibitors, prompting the US Food and Drug Administration to issue alerts on possible adverse effects.⁸ Acute pancreatitis is a severe clinical condition characterized by pancreatic pathological changes and increased serum amylase and lipase levels. Obstructive gallstone disease, alcohol abuse, hypertriglyceridemia, obesity, and type 2 diabetes mellitus are the most common risk factors for pancreatitis and pancreatic cancer.^9–11Although pancreatitis and pancreatic cancer have been suggested to be more frequent in diabetic patients treated with GLP-1–based therapies, the methodologically heterogeneous literature available does not support a firm conclusion on whether GLP-1 receptor agonists or DPP-IV inhibitors are directly implicated in pancreatitis or pancreatic cancer.^8,12–25 Animal studies designed to examine the effect of GLP-1–based therapies on exocrine pancreas have also yielded conflicting results.^26–31In this study, we directly evaluated whether the GLP-1 receptor agonist exenatide (EXE) can promote inflammation/pancreatitis and hyperplasia/dysplasia in exocrine pancreas of baboons. Baboons have interesting genetic and physiological similarity to humans, develop similar pathological features, and represent a valuable model to study human diseases, such as insulin resistance, obesity, and type 2 diabetes mellitus.^32–38     

Glucose-6-phosphate dehydrogenase variants: reexamination of G6PD Chicago and Cornell and a new variant (G6PD Pea Ridge) resembling G6PD Chicago

Two large and unrelated families were investigated for hereditary nonspherocytic hemolytic anemia associated with deficiency of erythrocyte glucose-6-phosphate dehydrogenase (G6PD). In both families, the kinetic and electrophoretic features of the G6PD variants resembled those of G6PD Chicago. Further investigation revealed that members of one of these families previously had been characterized as having the G6PD variants Chicago and Cornell. However, it is clear that each of these terms has been applied to the same variant in this single large kindred. In the second family, we describe a newly identified variant with unique characteristics, which we have designated G6PD Pea Ridge. G6PD Pea Ridge resembles G6PD Chicago but differs in electrophoretic mobility and in a few kinetic parameters. It exhibits an unusually high Ki for NADPH and thus appears to be insensitive to product inhibition. As other cases previously considered to be the Chicago variant become more fully characterized, this probably will be shown to be a heterogeneous group of variants.     

Demonstration of reversible priming of human neutrophils using platelet- activating factor

Exposure of neutrophils to agents such as lipopolysaccharide, tumor necrosis factor-alpha (TNF-alpha), and the granulocyte-macrophage colony-stimulating factor causes a major upregulation of subsequent agonist-induced NADPH oxidase activation. This priming effect is a prerequisite for neutrophil-mediated tissue damage and has been widely considered to be an irreversible process. We have investigated the potential for neutrophils to recover from a priming stimulus by studying the effects of platelet-activating factor (PAF). PAF did not stimulate respiratory burst activity directly, but caused a rapid (maximal at 10 minutes) and concentration-dependent (EC50 50.2 nmol/L) increase in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide anion release. At time-points > 10 minutes, this priming effect spontaneously declined, with return to basal levels of fMLP- stimulated superoxide anion generation by 120 minutes. An identical priming time-course was observed with N-methyl carbamyl PAF, a nonmetabolizable analogue of PAF, indicating that the transient nature of PAF-induced priming was not secondary to PAF metabolism. Two structurally diverse PAF receptor antagonists (UK-74,505 and WEB 2086), added 10 minutes after PAF addition, increased the rate of decay of the priming effect. In contrast, TNF-alpha-induced priming, which was of a similar magnitude to that observed for PAF, was slower to evolve (maximal at 30 minutes) and remained constant for at least 120 minutes. The reversible nature of PAF-induced priming was confirmed by demonstrating that PAF-, but not TNF-alpha-, induced cell polarization (shape change) and CD11b-dependent neutrophil binding of albumin-coated latex beads was also transient, with return to basal, unstimulated levels by 120 minutes. Furthermore, cells that had spontaneously deprimed following PAF exposure retained their capacity to be fully reprimed by a subsequent addition of either PAF or TNF-alpha. These data imply that neutrophil priming is not an irreversible event: the demonstration of a cycle of complete priming, depriming, and repriming offers the potential for functional recycling of neutrophils at sites of inflammation.     

Genetic and environmental influences on thyroid hormone variation in Mexican Americans

Thyroid hormones play major roles in the regulation of a wide range of metabolic and physiologic processes, but the genes and environmental factors that affect normal, quantitative variation in thyroid hormone concentrations are largely unknown. Using quantitative genetic methods, we evaluated the effects of genes and environmental factors on thyroid hormone variation in 586 women and 425 men from 27 randomly ascertained Mexican-American families from the San Antonio Family Heart Study. Data were available on free and total T(4), free and total T(3), TSH, thyroglobulin, and T(4)-binding globulin, as well as on covariates, including sex, age, weight, lifestyle habits, physical activity, and others. These covariates accounted for 2-18% of total phenotypic variation, whereas genes accounted for 26-64% of the variation. Overall, free T(3) had the highest heritability, which is noteworthy because it is the most biologically active thyroid hormone and accounts for the vast majority of metabolic and physiologic effects of thyroid hormones. Our results indicate that genes account for a substantial portion of variation in human thyroid hormone levels, and suggest that further studies to identify the genes involved in this variation could reveal important insights into the processes that govern thyroid-mediated metabolism.