Joshua I. Suhonen

University of Wisconsin–Madison

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Dawn Belt Davis

University of Wisconsin–Madison

Mary E. Rabaglia

University of Wisconsin–Madison

Jeremy A. Lavine

Northwestern University

Alan Attie

University of Wisconsin–Madison

Mark P. Keller

University of Wisconsin–Madison

Brian S. Yandell

University of Wisconsin–Madison

Kimberly A. Krautkramer

University of Gothenburg

Eric E. Schadt

Icahn School of Medicine at Mount Sinai

I‐Ming Wang

Pfizer (United States)

Jamie M. Sperger

University of Wisconsin–Madison

Cooperative Institutions

University of Wisconsin–Madison

Highland Community College - Illinois

Wisconsin Institutes for Discovery

Medical College of Wisconsin

UW Health University Hospital

Madison Group (United States)

William S. Middleton Memorial Veterans Hospital

University of Chicago

University of Wisconsin Carbone Cancer Center

National Institutes of Health

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FoxM1 Is Up-Regulated by Obesity and Stimulates β-Cell Proliferation

Endocrine Reviews (2010)

Dawn Belt Davis Jeremy A. Lavine Joshua I. Suhonen Kimberly A. Krautkramer Mary E. Rabaglia

β-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 β-cell mass, β-cell proliferation, and glucose homeostasis. We hypothesized that FoxM1 is up-regulated by nondiabetic obesity and initiates a transcriptional program leading to β-cell proliferation. We performed gene expression analysis on islets from the nondiabetic C57BL/6 Leptinob/ob mouse, the diabetic BTBR Leptinob/ob mouse, and an F2 Leptinob/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 β-cell mass expansion and proliferation. This up-regulation was absent in the diabetic strain. In the F2 Leptinob/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 β-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 are positively correlated with body mass index. Our data suggest that β-cell proliferation occurs in adult obese humans in an attempt to expand β-cell mass to compensate for insulin resistance, and that the FoxM1 transcriptional program plays a key role in this process.

FOXM1

10.1210/edrv.31.4.9981

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Appendiceal length as an independent risk factor for acute appendicitis

European Radiology (2013)

Perry J. Pickhardt Joshua I. Suhonen Edward M. Lawrence Alejandro Muñoz del Río B. Dustin Pooler

Neuroradiology

Interventional radiology

10.1007/s00330-013-2948-1

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FoxM1 Is Up-Regulated by Obesity and Stimulates β-Cell Proliferation

Molecular Endocrinology (2010)

Dawn Belt Davis Jeremy A. Lavine Joshua I. Suhonen Kimberly A. Krautkramer Mary E. Rabaglia

β-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 β-cell mass, β-cell proliferation, and glucose homeostasis. We hypothesized that FoxM1 is up-regulated by nondiabetic obesity and initiates a transcriptional program leading to β-cell proliferation. We performed gene expression analysis on islets from the nondiabetic C57BL/6 Leptinob/ob mouse, the diabetic BTBR Leptinob/ob mouse, and an F2 Leptinob/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 β-cell mass expansion and proliferation. This up-regulation was absent in the diabetic strain. In the F2 Leptinob/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 β-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 β-cell proliferation occurs in adult obese humans in an attempt to expand β-cell mass to compensate for insulin resistance, and that the FoxM1 transcriptional program plays a key role in this process.

FOXM1

10.1210/me.2010-0082

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FoxM1 Is Up-Regulated by Obesity and Stimulates β-Cell Proliferation

The Journal of Clinical Endocrinology & Metabolism (2010)

Dawn Belt Davis Jeremy A. Lavine Joshua I. Suhonen Kimberly A. Krautkramer Mary E. Rabaglia

through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions.To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the ␣-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic ␣-cell.Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production.Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

FOXM1

10.1210/jcem.95.8.9994

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

Frontiers in Neuroscience (2016)

Svyatoslav Vergun Wolfgang Gaggl Veena A. Nair Joshua I. Suhonen Rasmus M. Birn

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 (RNS) 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 resting state networks 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.

10.3389/fnins.2016.00440

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Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival

Endocrinology (2010)

Jeremy A. Lavine Philipp W. Raess Donald S. Stapleton Mary E. Rabaglia Joshua I. Suhonen

An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/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 α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-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 β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance.

Hyperinsulinemia

10.1210/en.2010-0233

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Citations (63)