A5089794744- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Genetic Mapping and Diversity in Plants and Animals
- Endoplasmic Reticulum Stress and Disease
- Genetic Associations and Epidemiology
- Gut microbiota and health
- Regulation of Appetite and Obesity
- Lipid metabolism and biosynthesis
- Cellular transport and secretion
- Diet, Metabolism, and Disease
- Peroxisome Proliferator-Activated Receptors
- Mitochondrial Function and Pathology
- Adipokines, Inflammation, and Metabolic Diseases
- Fatty Acid Research and Health
- Probiotics and Fermented Foods
- Genetics and Neurodevelopmental Disorders
- Infant Nutrition and Health
- Epigenetics and DNA Methylation
- Pancreatic and Hepatic Oncology Research
- Genomics and Chromatin Dynamics
- Diabetes and associated disorders
- Liver Disease Diagnosis and Treatment
- Cholesterol and Lipid Metabolism
- Drug Transport and Resistance Mechanisms
University of Wisconsin–Madison
2015-2025
The University of Texas Southwestern Medical Center
1993
Highlights•Host genotype affects the abundance of taxa associated with metabolic disease•Gut microbiota susceptibility to diet-induced disease•The gut microbiome modulates insulin secretionSummaryGenetic variation drives phenotypic diversity and influences predisposition disease. Here, we characterize phenotypes eight genetically distinct inbred mouse strains in response a high-fat/high-sucrose diet. We found significant diabetes-related composition among different dietary challenge...
Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences gene expression adipose tissue from lean, obese, obese-diabetic mice. The level over 11,000 transcripts was analyzed, 214 showed significant between lean obese Surprisingly, the genes normally associated adipocyte...
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor influences microbiota composition, mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones produced by chemically modified bacteria. BAs serve as environmental cues nutrients to microbes, but they can also have antibacterial effects. We hypothesized genetic in BA metabolism homeostasis influence...
The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial...
The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant diet- and leptin deficiency-induced obesity. BTBR mouse strain replicates many features of insulin resistance found humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that sensitivity was improved heart, soleus muscle, adipose tissue, liver SCD1-deficient mice. We next...
Coordinated regulation of gene expression levels across a series experimental conditions provides valuable information about the functions correlated transcripts. The consideration correlation over time or tissue dimension has proved in predicting function. Here, we consider correlations genetic dimension. In addition to identifying coregulated genes, also supplies us with genomic locations putative regulatory loci. We calculated among approximately 45,000 traits derived from 60 individuals...
Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue obese (ob/ob) mice, expression adipogenic genes decreased. When made genetically obese, BTBR mouse strain diabetes susceptible and C57BL/6J (B6) resistant. used DNA microarrays RT-PCR to compare gene BTBR-ob/ob versus B6-ob/ob mice tissue, liver, skeletal muscle, pancreatic islets. Our results show: 1) there an increased involved inflammation diabetic mice; 2) lipogenic...
Genetic susceptibility to type 2 diabetes is primarily due β-cell dysfunction. However, a genetic study directly interrogate function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on Western-style diet, and measured insulin secretion in response variety of secretagogues. Insulin DO ranged >1,000-fold even though none the were diabetic. The secretory each secretagogue had unique architecture; some loci specific for one...
The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the expression etiology diabetes, we sensitized genetically diverse mouse population Western diet high fat (45% kcal) and sucrose (34%) carried out genome-wide association mapping diabetes-related phenotypes. We quantified mRNA abundance islets identified 18,820 QTL. applied mediation analysis to identify candidate causal driver genes at affect numerous transcripts....
Mitochondrial proteins are replete with phosphorylation, yet its functional relevance remains largely unclear. The presence of multiple resident mitochondrial phosphatases, however, suggests that protein dephosphorylation may be broadly important for calibrating activities. To explore this, we deleted the poorly characterized matrix phosphatase Pptc7 from mice using CRISPR-Cas9 technology. Strikingly,
Abstract PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper content and function. Newborn mice lacking Pptc7 exhibit aberrant protein phosphorylation, suffer from range of metabolic defects, fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss in adult causes marked reduction mass capacity with elevated hepatic triglyceride accumulation. animals increased expression the mitophagy receptors BNIP3 NIX, -/- mouse...
We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lepob/ob and C57BL/6 (B6) mouse strains. Introgression of Chr into B6 mice resulted consomic with reduced fasting plasma insulin elevated glucose levels. derived panel sub-congenic narrowed susceptibility to 1.6 Mb region. this fragment lean (B6.16BT36–38) replicated phenotypes mice. Pancreatic islets B6.16BT36–38 were defective second phase secretion, suggesting...
We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from trans-Golgi network (TGN) vacuole. Whole-body KO mice, when made obese with leptin(ob) mutation (ob/ob), developed diabetes. β Cells these mice had severe deficiency of secretory granules (SGs) and insulin. Interestingly, single secretagogue challenge failed consistently elicit an insulin dysfunction. However,...
The membrane transporter AT-1/SLC33A1 translocates cytosolic acetyl-CoA into the lumen of endoplasmic reticulum (ER), participating in quality control mechanisms within secretory pathway. Mutations and duplication events are highly pleiotropic have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity seizures, dysmorphism. Despite these known associations, biology this key is only beginning be uncovered. Here,...
An absolute or functional deficit in β-cell mass is a key factor the pathogenesis of diabetes. We model obesity-driven expansion by studying diabetes-resistant C57BL/6-Leptinob/ob mouse. previously reported that cholecystokinin (Cck) was most up-regulated gene obese pancreatic islets. now show islet (CCK) 500-fold obesity and expressed both α- β-cells. bred null Cck allele into background investigated metabolic parameters Cck-deficient mice. Loss CCK resulted decreased size reduced through...
Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of candidate T2D-associated genes within these regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show ~40% linked to broad region on chromosome (Chr) 2. As all but 9 are not physically located Chr 2, linkage suggests genomic factor(s) regulates their trans. The...
In humans, nonalcoholic fatty liver disease (NAFLD) is the most prevalent due to increased prevalence of obesity. While treatment NAFLD often geared toward lifestyle changes, such as diet and exercise, use dietary supplements probiotics underinvestigated. Here, we report that probiotic Lactobacillus reuteri reduces in a mouse model diet-induced This phenotype was further enhanced upon delivery recombinant interleukin-22 by engineered . These observations pave road better understanding...
Abstract Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR C57BL/6J (B6) mice have normal responsiveness fasting plasma levels. However, cross between these two strains yielded male offspring severe Surprisingly, on basal (6.5% fat), was not hyperinsulinemia. 15% fat produced significant hyperinsulinemia in (twofold at 10 weeks; P <.05)....
Stearoyl-coenzyme A desaturase 1-deficient (SCD1−/−) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1−/− developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate LDL clearance was decreased VLF relative to SCD1+/+ mice, indicating that reduced apoB-containing contributed hypercholesterolemia. Additionally, HDL-cholesterol dramatically these mice....
Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream hepatocytes. In contrast, in extrahepatic tissues, microvasculature critically important insulin action, because transport across endothelial cell layer rate limiting insulin-stimulated glucose disposal. However, very little known concerning role this process pericytes, mural cells lining basolateral membrane cells. PDGF-B growth factor involved recruitment and function...
The advent of sophisticated genomic techniques for gene mapping and microarray analysis has provided opportunities to map mRNA abundance quantitative trait loci (QTL) throughout the genome. Unfortunately, simple each individual on scale a typical experiment is computationally intensive, subject high sample variance, therefore underpowered. However, this problem can be addressed by capitalizing correlation among large number traits. We present method reduce dimensionality expression data as...