A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity

<p>Abstract</p> <p>Background</p> <p>The genetic architecture of multifactorial traits such as obesity has been poorly understood. Quantitative trait locus (QTL) analysis is widely used to localize loci affecting multifactorial traits on chromosomal regions. However, large confidence intervals and small phenotypic effects of identified QTLs and closely linked loci are impeding the identification of causative genes that underlie the QTLs. Here we developed five subcongenic mouse strains with overlapping and non-overlapping wild-derived genomic regions from an F2 intercross of a previously developed congenic strain, B6.Cg-<it>Pbwg1</it>, and its genetic background strain, C57BL/6J (B6). The subcongenic strains developed were phenotyped on low-fat standard chow and a high-fat diet to fine-map a previously identified obesity QTL. Microarray analysis was performed with Affymetrix GeneChips to search for candidate genes of the QTL.</p> <p>Results</p> <p>The obesity QTL was physically mapped to an 8.8-Mb region of mouse chromosome 2. The wild-derived allele significantly decreased white fat pad weight, body weight and serum levels of glucose and triglyceride. It was also resistant to the high-fat diet. Among 29 genes residing within the 8.8-Mb region, <it>Gpd2, Upp2, Acvr1c, March7 </it>and <it>Rbms1 </it>showed great differential expression in livers and/or gonadal fat pads between B6.Cg-<it>Pbwg1 </it>and B6 mice.</p> <p>Conclusions</p> <p>The wild-derived QTL allele prevented obesity in both mice fed a low-fat standard diet and mice fed a high-fat diet. This finding will pave the way for identification of causative genes for obesity. A further understanding of this unique QTL effect at genetic and molecular levels may lead to the discovery of new biological and pathologic pathways associated with obesity.</p

Convergence of explicit p1 Finite-Element Solutions to Maxwell’s Equations

This paper is devoted to the numerical validation of an explicit finite-difference scheme for the integration in time of Maxwell’s equations in terms of the sole electric field. The space discretization is performed by the standard P1 finite element method assorted with the treatment of the time-derivative term by a technique of the mass-lumping type. The rigorous reliability analysis of this numerical model was the subject of authors’ another paper [2]. More specifically such a study applies to the particular case where the electric permittivity has a constant value outside a sub-domain, whose closure does not intersect the boundary of the domain where the problem is defined. Our numerical experiments in two-dimension space certify that the convergence results previously derived for this approach are optimal, as long as the underlying CFL condition is satisfied

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

All major cell types in pancreatic islets express the transforming growth factor (TGF)-β superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in β-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca2+ signaling in islet cells, with activin A increasing, but activin B decreasing, glucose-stimulated Ca2+ influx. On its own, activin B had no effect on WT cells, but stimulated Ca2+ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7−/− mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca2+ signaling in β-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting β-cell function by mediating the effects of activin B on Ca2+ signaling