Biomedical subjects

Samuel T Nadler

Publications and source records attributed to Samuel T Nadler.

4 recordsLinked to original sources

PubMed2006

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance.

Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 x BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity.

Abdominal Fat↗

PubMed2003

Dimension reduction for mapping mRNA abundance as quantitative traits.

The advent of sophisticated genomic techniques for gene mapping and microarray analysis has provided opportunities to map mRNA abundance to quantitative trait loci (QTL) throughout the genome. Unfortunately, simple mapping of each individual mRNA trait on the scale of a typical microarray experiment is computationally intensive, subject to high sample variance, and therefore underpowered. However, this problem can be addressed by capitalizing on correlation among the large number of mRNA traits. We present a method to reduce the dimensionality for mapping gene expression data as quantitative traits. We used a blind method, principal components, and a sighted method, hierarchical clustering seeded by disease relevant traits, to define new traits composed of a small collection of promising mRNAs. We validated the principle of our approach by mapping the expression levels of metabolism genes in a population of F(2)-ob/ob mice derived from the BTBR and C57BL/6J strains. We found that lipogenic and gluconeogenic mRNAs, which are known targets of insulin action, were closely associated with the insulin trait. Multiple interval mapping and Bayesian interval mapping of this new trait revealed significant linkages to chromosome regions that were contained in loci associated with type 2 diabetes in this same mouse sample. As a further statistical refinement, we show that principal component analysis also effectively reduced dimensions for mapping phenotypes composed of mRNA abundances.

Animals↗

PubMed2003

Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility.

Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes.

Adipose Tissue↗

PubMedDate not supplied

Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes.

The BTBR mouse strain harbors alleles promoting insulin resistance. When made genetically obese (ob/ob), these mice develop severe type 2 diabetes (fasting glucose >400 mg/dL). By contrast, C57BL/6 ob/ob mice are able to compensate for the obesity-induced insulin resistance by increasing pancreatic insulin secretion and thus maintain only slightly elevated plasma glucose levels (<250 mg/dL). Islet insulin secretory responses to glucose are undiminished in the remaining islets of BTBR ob/ob mice. A genome-wide linkage analysis identified 3 major loci influencing plasma glucose and/or insulin levels in an F2ob/ob sample derived from the 2 strains. A locus on chromosome 2 affects insulin sensitivity and is independent of obesity. Loci on chromosomes 16 and 19 affect fasting glucose and insulin levels and likely affect beta-cell mass or function. Analysis of mRNA expression patterns revealed a reduction in lipogenic gene expression in adipose tissue associated with obesity. Conversely, hepatic lipogenic gene expression increases in obese mice, but to a much greater extent in the diabetes-resistant C57BL/6 strain. We propose that hepatic lipogenic capacity affects susceptibility to obesity-induced diabetes.

Animals↗