Classification and Extraction of Resting State Networks Using Healthy and Epilepsy fMRI Data.

Functional magnetic resonance imaging studies have significantly expanded the field's understanding of functional brain activity of healthy and patient populations. Resting state (rs-) fMRI, which does not require subjects to perform a task, eliminating confounds of task difficulty, allows examination of neural activity and offers valuable functional mapping information. The purpose of this work was to develop an automatic resting state network (RSN) labeling method which offers value in clinical workflow during rs-fMRI mapping by organizing and quickly labeling spatial maps into functional networks. Here independent component analysis (ICA) and machine learning were applied to rs-fMRI data with the goal of developing a method for the clinically oriented task of extracting and classifying spatial maps into auditory, visual, default-mode, sensorimotor, and executive control RSNs from 23 epilepsy patients (and for general comparison, separately for 30 healthy subjects). ICA revealed distinct and consistent functional network components across patients and healthy subjects. Network classification was successful, achieving 88% accuracy for epilepsy patients with a naïve Bayes algorithm (and 90% accuracy for healthy subjects with a perceptron). The method's utility to researchers and clinicians is the provided RSN spatial maps and their functional labeling which offer complementary functional information to clinicians' expert interpretation.

FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation.

beta-Cell mass expansion is one mechanism by which obese animals compensate for insulin resistance and prevent diabetes. FoxM1 is a transcription factor that can regulate the expression of multiple cell cycle genes and is necessary for the maintenance of adult beta-cell mass, beta-cell proliferation, and glucose homeostasis. We hypothesized that FoxM1 is up-regulated by nondiabetic obesity and initiates a transcriptional program leading to beta-cell proliferation. We performed gene expression analysis on islets from the nondiabetic C57BL/6 Leptin(ob/ob) mouse, the diabetic BTBR Leptin(ob/ob) mouse, and an F2 Leptin(ob/ob) population derived from these strains. We identified obesity-driven coordinated up-regulation of islet Foxm1 and its target genes in the nondiabetic strain, correlating with beta-cell mass expansion and proliferation. This up-regulation was absent in the diabetic strain. In the F2 Leptin(ob/ob) population, increased expression of Foxm1 and its target genes segregated with higher insulin and lower glucose levels. We next studied the effects of FOXM1b overexpression on isolated mouse and human islets. We found that FoxM1 stimulated mouse and human beta-cell proliferation by activating many cell cycle phases. We asked whether FOXM1 expression is also responsive to obesity in human islets by collecting RNA from human islet donors (body mass index range: 24-51). We found that the expression of FOXM1 and its target genes is positively correlated with body mass index. Our data suggest that beta-cell proliferation occurs in adult obese humans in an attempt to expand beta-cell mass to compensate for insulin resistance, and that the FoxM1 transcriptional program plays a key role in this process.

Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival.

An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/ob) mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.