Project description:The cannabinoid 1 receptor (CB1) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1 is expressed on pancreatic beta (β)-cells where its functions have not been fully described. We generated a β-cell-specific CB1-knockout (β-CB1-/-) mouse to study the long-term consequences of CB1 ablation on β-cell function in adult mice. β-CB1-/- mice had increased basal- and stimulated-insulin secretion and intra-islet cAMP levels, resulting in primary hyperinsulinemia, as well as increased β-cell viability, proliferation, and islet area. Hyperinsulinemia led to insulin resistance, which was aggravated by a high fat/high glucose diet and weight gain, although β-cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from β-CB1-/- mice were protected from diet-induced inflammation. Mechanistically we show that this is a consequence of curtailment of oxidative stress and reduced activation of Nlrp3 inflammasome in β-cells. Our data demonstrate CB1 to be a negative regulator of β-cells and a mediator of islet inflammation under conditions of metabolic stress.
Project description:Zinc finger protein ZBTB20 plays a critical role in regulating insulin expression from islet beta-cells by orchestrating their gene expression profile. We used microarrays to investigate the target gene of ZBTB20 in mouse pancreatic beta-cells. Adult mouse islets were harvested for RNA extraction and hybridization on Affymetrix microarrays. We sought to identify the target genes of transcription factor ZBTB20 in beta-cells. To that end, we isolated the islets from adult beta cell-specific ZBTB20 knockout and their littermate control mice.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:To determine the role of Ascl1 in beta cell development, function, and metabolic stress response, we generated beta cell specific Ascl1 knockout mice and assessed their glucose homeostasis, islet morphology, and gene expression after feeding a normal diet, a high fat diet (HFD) for 12 weeks, or on a background of Abcc8 (KATP channel subunit) knockout mice. For the RNA-seq analysis, islets from male Ascl1betaKO and littermate control mice (N = 4 for each genotype and condition) were collected from three different conditions: 1) normal diet fed 2) HFD fed for 12 weeks, 3) on a background of homozygous Abcc8 allele.
Project description:Objective: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and -cell knockout islets. Results: HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions: HDAC3 plays an important role in regulating insulin secretion in vivo and therapeutic intervention may improve glucose homeostasis.